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The past, present and future perspectives of matrix metalloproteinase inhibitors
Journal Pre-proof The past, present and metalloproteinase inhibitors
future
perspectives
of
matrix
Kang Li, Franklin R. Tay, Cynthia Kar Yung Yiu PII:
S0163-7258(19)30217-7
DOI:
https://doi.org/10.1016/j.pharmthera.2019.107465
Reference:
JPT 107465
To appear in:
Pharmacology and Therapeutics
Please cite this article as: K. Li, F.R. Tay and C.K.Y. Yiu, The past, present and future perspectives of matrix metalloproteinase inhibitors, Pharmacology and Therapeutics(2019), https://doi.org/10.1016/j.pharmthera.2019.107465
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© 2019 Published by Elsevier.
Journal Pre-proof
P&T 23637 The Past, Present and Future Perspectives of Matrix Metalloproteinase Inhibitors Article Type: Review Article
Kang Li1 , Franklin R. Tay2 *, Cynthia Kar Yung Yiu1 *
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1. Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of
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Hong Kong, Prince Philip Dental Hospital, 34 Hospital Road, Sai Ying Pun, Hong
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Kong
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2. College of Graduate Studies, Augusta University, Augusta, GA, USA
Email: [email protected]; [email protected] (*co-corresponding authors)
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Tel: +852 28590256
Declaration:
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Fax: +852 25593803
The article titled “The Past, Present and Future Perspectives of Matrix Metalloproteinase Inhibitors” has not been published and is not under consideration for publication elsewhere.
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Abstract: Matrix metalloproteinases (MMPs) are a large family of enzymes that degrade the extracellular matrix (ECM). Under pathologic conditions, overexpression of MMPs or insufficient control by tissue inhibitors of MMPs (TIMPs) results in the dysregulation of tissue remodeling and causes a variety of diseases such as encephalomyelitis, rheumatoid arthritis, Alzheimer’s disease and tumors. Therefore,
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the high affinity of MMPs for biomolecules renders them attractive targets for
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inhibition when homeostasis breaks down in the ECM. There are 4 generations of
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MMP inhibitors (MMPIs), ranging from small molecules or peptides to antibodies and
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protein-engineered inhibitors of metalloproteinase. Although a plethora of MMPIs has
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been synthesized, most of them have failed in clinical trials or are still in the laboratory stage of development. The present review summarizes the development of
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MMPIs, their associated problems and discusses future directions for the development
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of the future generations of MMPIs.
Key Words: Matrix metalloproteinase; MMP; Inhibitor; MMPI
Journal Pre-proof Table of Contents: 1. Introduction 2. Historical generations of MMPIs 2.1 First generation – hydroxamate-based inhibitors 2.2 Second generation – non-hydroxamate-based inhibitors 2.3 Third generation – catalytic domain (non-zinc binding) inhibitors 2.4 Fourth generation -- allosteric and exosite inhibitors 3. On-going research techniques
3.2 Protein-engineered inhibitors
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4.1 Enhancing binding site specificity
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4. Future prospects of next generation of MMPIs
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3.1 Antibody-based inhibitors
4.2 Smart drug delivery systems for achieving selectivity
5. Concluding remarks
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References
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Conflict of interest statement
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4.3 Thorough understanding of MMPs in health and disease
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Abbreviations: ADAM, a disintegrin and metalloproteinase; ADAMTS, ADAM with thrombospondin motifs; bid, twice daily; COPD, chronic obstructive pulmonary disease; ECM, extracellular matrix; FDA, Food and Drug Administration; GPI, glycophosphatidylinositol; IV, intravenous injection; mAb, monoclonal antibody; MMP, Matrix metalloproteinase; MMPI, Matrix metalloproteinases inhibitor; MSS, musculoskeletal syndrome; MT, membrane-type; NSCLC, non-small-cell lung cancer; N-TIMP, N-terminal peptide of TIMP; PDB, Protein Data Bank; qd, once daily; SC, subcutaneous administration; SCLC, small-cell lung cancer; TDP, time to disease progression; tid, three times daily; TIMP, tissue inhibitors of MMP.
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1. Introduction Matrix metalloproteinases (MMPs) were first discovered in 1962 by Gross and Lapiere in the tail of tadpole during frog metamorphosis (Gross and Lapiere, 1962). These enzymes have been recognized as the major proteolytic enzymes for regulating extracellular matrix (ECM) degradation (Gross, 2004). To date, 23 MMPs have been
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identified in humans. Apart from their tissue-remodeling function, MMPs also
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participate in regulating many non- matrix targets, such as cell surface receptors,
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proteinases (Vanlaere and Libert, 2009).
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cell-cell adhesion molecules, cytokines, clotting factors, chemokines and other
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Matrix metalloproteinases may be classified in two different ways, based on substrate or domain organization. The substrate classification is more common and
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categories MMPs into collagenases (MMP-1, MMP-8, and MMP-13), gelatinases
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(MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, and MMP-11), matrilysins
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(MMP-7 and MMP-26), membrane-type (MT) MMPs (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25) and others (MMP-12, MMP-19, MMP-20, MMP-21, MMP-23, MMP-27, and MMP-28) (Visse and Nagase, 2003). Many studies have pointed out the limitation of this classification. For example, MMP-1, designated as a collagenase, also cleaves tenascin and aggrecan; MMP-2, a gelatinase, also degrades fibronectin, aggrecan and non-ECM substrates. Even MMP-14, a well-known MT1-MMP, serves as a collagenase (Chakraborti et al., 2003; Tam et al., 2004). The easily misleading names and the unclassified MMPs have limited the accuracy of substrate-based classification.
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An alternative classification of MMPs has been proposed based on their domain organization. In this classification, MMPs may be divided into archetypal MMPs, matrilysins, gelatinases and furin-activable MMPs (Fanjul-Fernández et al., 2010; Vandenbroucke and Libert, 2014) (Fig. 1). All MMPs share some common domain structures (except MMP-7, MMP-23, and MMP-26). The signal peptide mediates
This intramolecular cysteine-switch keeps MMPs in their
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with a cysteine residue.
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MMP secretion. The pro-peptide protects the Zn2+ binding site through interaction
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latent, inactive pro- forms until cleavage of the pro-peptide domain. The catalytic
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domain, which contains Zn2+, is responsible for substrate hydrolysis. The hemopexin
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domain, which is linked to catalytic domain via a flexible hinge, is responsible for
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substrate recognition and dimerization (Aureli et al., 2008; Tallant et al., 2010). Fig.1 Structural classification of MMPs based on their domain arrangement and the relationship with other metzincins superfamily members
Apart from the commonly-shared structures, there are features which are characteristic of individual MMPs. These characteristics include: (1) MMP-7 and MMP-26 lack the hinge region and the hemopexin domain; (2) MMP-2 and MMP-9
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contain three fibronectin type II motifs (aka. collagen binding domain) on the catalytic site; (3) furin-activable MMPs have a furin cleavage motif between the
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pro-peptide and catalytic domain; (4) MT-MMPs have a transmembrane domain or
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glycophosphatidylinositol (GPI) anchor on their C-terminus; and (5) MMP-23 lacks
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the signal peptide, the cysteine-switch motif and the hemopexin domain. The structure of ECM is not static. Under normal conditions, MMPs and
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endogenous tissue inhibitors of MMPs (TIMPs) mutually participate in the
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homeostasis of the ECM (Overall and López-Otín, 2002; Woolley et al., 1975). The
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TIMP family consists of four members, namely TIMP1-4, which were first identified in serum and tissue culture (Bauer et al., 1975; Eisen et al., 1971). Each TIMP forms a 1:1 complex with MMP in a non-selective manner (Maskos and Bode, 2003). The three-dimensional structures
of
TIMP-MMP
complexes
stipulate
that
the
wedge-shaped ridge of the N-terminal peptide of TIMP (N-TIMP, consisting of approximately 126 amino acids) interacts with the Zn2+ of MMP active site through the α-amino and carbonyl groups. In addition, the serine/threonine group of N-TIMP interacts with the nucleophilic glutamine in the MMP catalytic site and activates the hydrolysis process (Mohan et al., 2016). Under pathologic conditions, overexpression
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of MMPs or insufficient control by TIMPs results in the dysregulation of tissue remodeling and causes a variety of diseases, such as encephalomyelitis (Mohan et al., 2016), rheumatoid arthritis (Ahrens et al., 1996), Alzheimer’s disease (Peress et al., 1995) and tumors (Coussens et al., 2002). Hence, MMPs are often considered valuable drug targets. A plethora of MMP inhibitors (MMPIs) have been designed for
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the purpose of restoring tissue homeostasis and curing diseases.
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As early as 1988, Reich et al. used a hydroxamic acid compound (SC-44463) to
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block collagenase and prevent metastasis in mouse models, which initiated the era of
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MMP inhibition therapeutics. Following that seminal study, clinical trials commenced
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with great enthusiasm and expectations on the first generation MMPIs (such as Batimastat, Marimastat, MMI-270 and Prinomastat) (Table 1). However, after nearly
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30 years of trials and tribulations, only one drug (Periostat®, doxycycline hydrate) had
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obtained approval from the US Food and Drug Administration (FDA) for the
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treatment of periodontal disease (Golub et al., 2001; Preshaw et al., 2004; Wynn, 1999). Accordingly, the objective of the present review is to provide a summary of the historical generations of MMPIs as well as the lessons acquired from those developments. This is followed by reviewing the latest research directions on MMPI synthesis, and finally, perspectives on the development of future generations of MMPIs.
2. Historical generations of MMPIs 2.1 First generation – hydroxamate-based inhibitors
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The first generation MMPIs are mainly small molecules or peptides containing the hydroxamate zinc-binding group (-CONHOH), which shows strong interaction with the Zn2+ ion on the catalytic domain of MMPs (Whittaker et al., 1999). The active
site
of
all
MMPs
shares
a
highly-conserved
sequence
motif
(His-Glu-Xxx-Gly-His-Xxx-Xxx-Gly-Xxx-Xxx-His). Because the three histidine
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residues form coordinate bonds with the catalytic Zn2+ ion, the hydroxamate group
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has the capability of inhibiting a broad-spectrum of MMPs (Bode et al., 1999). For
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example, Batimastat, the first MMPI to enter clinical trials for cancer, inhibits MMP-1,
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-2, -7, and -9 (Wojtowicz-Praga et al., 1996). However, due to its poor oral
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bioavailability, Batimastat was superseded by Marimastat, which retained the property of its predecessor, but manifested better oral bioavailability (Nemunaitis et al., 1998).
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Prinomastat, another hydroxamate-based inhibitor, shows high affinity toward
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MMP-2, -3, -9, -13, and -14 over MMP-1 (Hande et al., 2004).
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Although animal-derived pre-clinical results of these hydroxamate-based inhibitors were fairly promising (Davies et al., 1993; Giavazzi et al., 1998), all subsequent clinical trials failed because of several reasons. Firstly, severe side effects such as musculoskeletal syndrome (MSS) and inflammation occurred in patients, which were not observed in the pre-clinical models (Skiles et al., 2004). These side effects were probably attributed to the broad-spectrum inhibiting property of the hydroxamate group. This group also inhibits the ADAMs (a disintegrin and metalloproteinase) family and ADAMTSs (ADAMs with thrombospondin motifs) family, two large related families of MMPs (Fig. 1), which play important roles in
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cellular regulation, cell- matrix interactions and membrane protein shedding (de Arao Tan et al., 2013; Edwards et al., 2008). Secondly, cancer patients who enrolled in the clinical trials were mostly at the advanced stage of the disease. By contrast, animal models that are utilized in the pre-clinical studies manifested only the early stage of cancer. While MMPs produced by stromal cells are important during the early aspects
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of cancer progression (i.e. local invasion), they may no longer be required once
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metastases have been established (Zucker et al., 2000). Thirdly, hydroxamate-based
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inhibitors were labile and unstable; their rapid clearance rate and short half- lives
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hindered their clinical application (Peng et al., 1999).
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2.2 Second generation – non-hydroxamate-based inhibitors
Fig. 2 Schematic representation of four zinc-binding groups (a: hydro xamate, b: thiolate, c: carbo xylate, and d: phosphinate) in complex with the zinc ion
To solve the problems associated with first generation MMPIs, the pharmaceutical industry began to shift its attention to non- hydroxamate-based inhibitors such as thiolate, carboxylate and phosphinate (Fig. 2) (Devel et al., 2010).
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The most significant difference between non-hydroxamate-based inhibitors and hydroxamate-based inhibitors is their affinity for the catalytic Zn2+ ion. The hydroxamate is a strong Zn2+-chelating group, which anchors itself tightly to the Zn2+ ion. This strong anchoring mechanism hinders the free orientation of the rest of the compound. On the contrary, the non-hydroxamate group is a relatively weak
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Zn2+-chelating group. Although there is some reduction of the inhibitor ’s potenc y, this
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weak binding property reduces off-target binding to the ADAMs and ADAMTSs
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families, thereby preventing side effects to a certain extent (Skiles et al., 2001). As
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reported by Overall and Kleifeld (2006a), introduction of the hypophosphite group
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increased the selectivity towards MMP-1 (Ki = 5 nM), compared with MMP-7 (Ki = 78 nM) by one order of magnitude. Likewise, introduction of the carboxylate group
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increased MMP selectivity by two orders of magnitude (Ki = 2 nM for MMP-1 and Ki
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= 850 nM for MMP-7). Despite these improvements, it is now well accepted that an
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ideal MMP-selective inhibitor should increase the difference in Ki over targets by three log orders. This is difficult to achieve in the catalytic zinc sites because of their highly homogeneous sequences (Overall and Kleifeld, 2006a). Clinical results conducted on non- hydroxamate-based inhibitors were mixed with success and failure. Because of their weak Zn2+-chelating ability, the rates of severe MSS decreased dramatically compared with the hydroxamate-based inhibitors. Although this was extremely encouraging, the invalid and even negative treatment effects of most non- hydroxamate-based inhibitors (except doxycycline) still casted a shadow on the ongoing and future clinical trials (Table 1). For example, Tanomastat,
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which contains a thioether zinc-binding group, had no serious MSS reported, but efficacy was invalid and even negative results were detected compared with the placebo arm in small-cell lung cancer patients (Erlichman et al., 2001; Hirte et al., 2006; Moore et al., 2003; Rigas et al., 2003). Metastat (COL-3), a tetracycline derivative inhibitor, had contradictory treatment effects in different diseases, and the
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high rates of photosensitivity reaction despite fastidious sun protection hindered the
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enthusiasm for pharmaceutical companies to proceed to Phase III trials (Chu et al.,
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2007; Cianfrocca et al., 2002; Rudek et al., 2001). Rebimastat (BMS-275291)
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(Douillard et al., 2004; Leighl et al., 2005; Miller et al., 2004; Rizvi et al., 2004),
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S-3304 (Chiappori et al., 2007; Van Marle et al., 2005) and AZD1236 (Dahl et al., 2012; Magnussen et al., 2011) all showed good tolerability, but no improved survival
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and convincing treatment effects were observed (Table 1).
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Setting all these failures aside, the only MMPI which gave people relief was
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doxycycline. As mentioned above, the Periostat® (doxycycline at sub-antimicrobial dose - 20 mg twice daily) is the only MMPI approved by FDA to date. Except for its outstanding performance in treating periodontitis, doxycycline at different dose levels also exhibited acceptable therapeutic effects in treating aortic aneurysms, multiple sclerosis as well as type II diabetes (Baxter et al., 2002; Frankwich et al., 2012; Minagar et al., 2008). Further Phase III trials are needed in larger populations to provide stronger evidence.
2.3 Third generation – catalytic domain (non-zinc binding) inhibitors Learning from the limitations of the former two generations of MMPIs, scientists
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began to shy away from the scope of the zinc binding group and target the catalytic domain of MMPs instead. In addition to the zinc binding site, the catalytic domain contains many other recognition pockets, half of which are on the r ight side of the Zn2+ ion (called primed side, with pockets named S 1 ’, S2 ’, S3 ’) and the other half on the left side (called unprimed side, with pockets named S 1 , S2 , S3 ) (Fig. 3a). The part of substrates or inhibitors that can fit into the S n pocket is named Pn accordingly (for
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example, P1 ’ fits in S1 ’, P2 fits in S2 ) (Whittaker et al., 1999). Among these
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recognition pockets, S1 ’ varies the most among different MMPs in the amino acid
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sequence and pocket depth. Consequently, the ranking of the selectivity of the
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recognition pockets toward substrates or inhibitors are: S1 ’ > S2 , S3 , S3 ’ > S1 > S2 ’ (Aureli et al., 2008; Pirard, 2007). Based on the depth of S1 ’ pocket or S1 ’ cavity (Fig.
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3c), MMPs may be separated into shallow (MMP-1, -7), intermediate (MMP-2, -8, -9),
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and deep pocket (MMP-3, -11, -12, -13, -14) (Aureli et al., 2008; Jacobsen et al., 2010;
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Park et al., 2003). The difference has been utilized in developing selective MMPIs. For example, inhibitors with a long P 1 ’ substituent like aromatic groups can fit in the large deep pocket of MMP-3, but are not accessible to MMP-1 and -7 because of their limited pocket depth (Terp et al., 2002). This method increased the selectivity to some extent; however, the intermediate and other similar deep pocket MMPs cannot be distinguished by simply elongating the P1 ’ substituent. With the development of X-ray crystallography, nuclear magnetic resonance spectroscopy, high-throughput screening and computational methods, structural differences in the S1 ’ pocket depth have been gradually recognized. A variety of
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highly-selective MMPIs with up to three orders of magnitude inhibition capacity have been developed (Matter and Schudok, 2004; Overall and Kleifeld, 2006a; Rao, 2005). For example, Pochetti et al. (2009) reported a selective inhibitor of MMP-8, which
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Pr
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pr
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induces a conformational change of the S 1 ’ loop (Fig. 3b). This, in turn, exposed an
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Pr
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pr
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extra binding region of the pocket by switching of the Y227 side chain, thereby improving the selectivity of MMP-8 (IC50 = 7.4 nM). Engel et al. (2005) identified another selective inhibitor, the pyrimidine dicarboxamide, which not only binds to the deep S1 ’ pocket of MMP-13, but also protrudes into a side pocket of S 1 ’, a feature that
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has not been observed in other MMPs (Fig. 3d). This observation led to an improved IC50 of 8 nM toward MMP-13 and against MMP-1, -2, -3, -7, -8, -9, -10, -12, -14, and -16 (IC50 > 100 μM). Inspired by the work of Engel et al. (2005), Gege et al. (2012) synthesized a highly-selective MMP-13 inhibitor with IC 50 = 0.03 nM, which is 20,000-fold over other MMPs.
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Fig. 3 Representation of the X-ray structure of MMP catalytic domain. The Zn 2+ appears as a
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purple dot. (a) The general location of S 3 -S3 ’ pockets indicated by circles (PDB code: 2OY4,
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uninhibited human MMP-8). (b) The indication of S 1 ’ loop, which is conformational flexible (PDB
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code: 3DPE, the complex between MMP-8 and a non-zinc chelating inhibitor). (c) The inhibitor is
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highlighted to indicate the S 1 ’ pocket depth (PDB code: 3DPE, the complex between MMP-8 and a non-zinc chelating inhibitor). (d) The inhibitor is highlighted to indicate its protrusion into S 1 ’
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Protein Data Bank.
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side pocket (PDB code: 1XUD, MMP-13 complexed with non-zinc binding inhibitor). PDB:
Apart from the synthesized MMPIs, many natural compounds have also been shown to possess selective inhibition via adaptation with specific MMP pockets. Wang et al. (2012) identified 19 potential MMPIs from 4,000 natural compounds isolated from 100 medicinal plants using structure-based virtual screening. After further testing, two classes of natural compounds (namely, caffeates and flavonoids) were found to have selective inhibition ability against MMP-2 and MMP-9 by occupying the S1 ’ and S3 pockets (Wang et al., 2012). Apart from plant-derived natural compounds, marine natural products are another huge pharmacological
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resource that have great potential in targeting MMPs (Gentile and Liuzzi, 2017). The major MMPIs of the marine environment are derivatives from algae, sponges and cartilage, such as Neovastat, Dieckol, Ageladine A and chitin. The y all manifest anti-angiogenic, anti-proliferative and anti-tumor effects to some extent (Agrawal et al., 2018).
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Compared with synthetic MMPIs, natural MMPIs are more bio- friendly and less toxic.
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However, they still have several drawbacks. Firstly, the effective dosage of most
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natural MMPIs lie in micromolar scale, which is thousands of times higher than the
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third generation synthetic MMPIs, not to mention the forthcoming protein-engineered
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MMPIs which lie in the picomolar scale (Arkadash et al., 2017; Engel et al., 2005; Gege et al., 2012). Despite the reduced cytotoxicity for natural MMPIs per unit, the
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overall side-effects on human subjects still require further evaluation via
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well-designed clinical trials. Secondly, some natural compounds that possess
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anti-MMP effects are mixtures derived from plants or the marine environment, such as the grape seed extract and Neovastat (isolated from shark cartilage). They have encountered the same challenges as with Chinese medicine, in that the effective chemical molecule cannot be defined. Consequently, even though the Phase II clinical trials were successful, the inability to set proper surrogate markers prevented the detection of potential clinical benefits in the Phase III clinical trials (Batist et al., 2002; Latreille et al., 2003; C. Lu et al., 2010). Thirdly, because it is difficult to patent these natural compounds, pharmaceutical companies and other investors are reluctant to sponsor large-scale clinical trials. Hence, data collected for potential natural MMPIs
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are inadequate to support their superiority over synthetic MMPIs.
2.4 Fourth generation -- allosteric and exosite inhibitors Apart from the catalytic domain, MMPs contain other distal structures such as the hemopexin domain, the collagen binding domain and the pro-peptide domain. Because these domains are far remote from the catalytic domain, previous research
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had not devoted much attention to their behaviors. As the full- length MMP structures are gradually unveiled, the functions of these additional domains in substrate
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recognition, signal transmission as well as protein-protein interactions are gradually
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recognized. These non-catalytic domains may be further utilized in designing
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selective MMPIs (Sela-Passwell et al., 2010).
Journal Pre-proof Table 1 Summary of MMP Inhibitors Clinical Trials MMPI name Batimastat
Structure Hydroxamate
Year 1996
Disease
Stage
Malignant tumors
Phase I
Treatment
(BB-94)
600,
Marimastat
1,200,
1,800
mg/m
2
via
Results
References
Mainly local toxicities, especially abdominal discomfort.
Wojtowicz-Praga
intraperitoneal injection Hydroxamate
1998
Malignant tumors
Phase I/II
(BB-2516) 2001
Pancreatic cancer
Phase III
et
al., 1996
5 mg to 100 mg bid or 5 mg to 25 mg
MSS increased in dosage over 50 mg bid after 1 month
qd
usage. Recommend 10 and 25 mg bid.
1998
5, 10, 25 mg bid vs. gemcitabine
1-year survival rate: 25 mg = gemcitabine > 10 mg = 5 mg;
Bramhall et al., 2001
f o
ro
Nemunaitis
et
al.,
MSS: 44% of marimastat > 12% of gemcitabine. 2002
Pancreatic cancer
Phase III
2002
Gastric cancer
Phase III
Gemcitabine with 10 mg bid or
-p
placebo
2004
MMI-270
Hydroxamate
2001
Metastatic breast cancer
Advanced solid cancer
Phase III
Prinomastat
Hydroxamate
2004
J
Advanced cancer
(AG3340) 2005
2006
NSCLC (Stage IIIB or IV)
Resectable
esophagus
Phase I
Phase I
Biphenyl,
(Bay 12-9566)
thioether
2001
Solid tumor
tolerated.
al., 2002
Positive treatment effect. Severe MSS observed.
Bramhall,
No difference in treating effects. MSS was associated with
Hallissey,
et al., 2002 Sparano et al., 2004
inferior survival. Rash and MSS observed in doses ≥ 300 mg bid. No
50 mg qd to 600 mg tid
5-fluorouracil
Bramhall, Schulz, et
Levitt et al., 2001
obvious tumor response. The recommended Phase II dose was 300 mg bid. +
folinic
acid
+
Severe MSS observed in 300 mg bid. Six patients (18.2%)
MMI-270 (50 mg qd, 150 mg tid or
had a partial response and 17 patients (51.5%) had stable
300 mg bid)
disease.
1 mg to 100 mg bid
No tumor response. 5-10 mg bid were recommended for
Eatock et al., 2005
Hande et al., 2004
longer treatment. Phase III
Phase II
cancer (Stage II or higher) Tanomastat
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Colorectal cancer
e r P
10 mg bid vs. placebo
Phase I
(CGS27023A)
2005
10 mg bid vs. placebo
No treatment effect; gemcitabine + marimastat was well
Phase I
Gemcitabine + cisplatin with 15 mg
Terminated early because of lack of treatment efficacy.
bid or placebo
MSS incidence increased.
5-FU + cisplatin + paclitaxel with 15
Early termination due to unexpected thromboembolic
mg bid or placebo
events. No definitive conclusions were obtained.
400 mg qd, 400 mg bid, 400 mg tid
Toxicity was mild. No MSS. No tumor responses. Due to
and 800 mg bid.
the low toxicity, 800 mg bid could be further tested.
Donald et al., 2005
Heath et al., 2006
Erlichman et al., 2001
Journal Pre-proof zinc-binding group 2003
SCLC and NSCLC
Phase III
800 mg bid vs. placebo
For NSCLC, the TDP was significantly increased.
Rigas et al., 2003
However, for SCLC, the TDP was significantly decreased. 2003
Pancreatic cancer without
Phase III
800 mg bid vs. gemcitabine
Early termination due to the poorer survival. Both arms had
prior chemotherapy 2006
Moore et al., 2003
low rates of serious toxicity.
Ovarian cancer with prior
Phase III
f o
Early termination due to Bayer’s decision. Well tolerated
800 mg bid vs. placebo
effective treatment
Hirte et al., 2006
without grade 3 or 4 adverse events, but has no positive
ro
treatment effects. Metastat
Tetracycline
(COL-3)
derivatives
2001
Refractory solid tumors
36, 50, 70, and 98 mg/m 2 qd.
Phase I
AIDS-Related
Kaposi’s
Phase I
25, 50 and 70 mg/m
sarcoma
2007
Cianfrocca
Significant change in MMP-2 levels.
2002
50 mg/m qd, and instructed to apply
Photosensitivity reaction despite fastidious sun protection.
Chu et al., 2007
sun protection procedures.
No obvious treatment effects.
20 mg bid (sub-antimicrobial dose) or
Well tolerability. Outstanding effects without causing
placebo
dysbacteriosis.
20 mg bid (sub-antimicrobial dose) or
Well
placebo
outcomes.
100 mg bid
Well tolerability. No significant change in aneurysms
r P
qd, and
instructed to apply sun protection
Advanced
soft
tissue
sarcoma 2001
Periodontitis
2004
Periodontitis
al
Phase II
n r u
derivatives
Phase II/III
2002
2
Photosensitivity reaction. Overall response rate was 44%.
procedures.
Tetracycline
p e
Rudek et al., 2001
recommended.
2002
Doxycycline
High rates of cutaneous phototoxicity. 36 mg/m2 qd was
o J
Asymptomatic abdominal
Phase III
Phase II
2
aortic aneurysms
tolerability.
Significantly
improvement
in
all
et
al.,
Golub et al., 2001
Preshaw et al., 2004
Baxter et al., 2002
diameter, but significant reduction in plasma MMP-9 level after 6 months treatment.
2008
Multiple sclerosis
Phase II
Interferon beta-1a with doxycycline
The therapy was effective, safe and well-tolerated.
Minagar et al., 2008
Doxycycline decreas ed inflammation and improved insulin
Frankwich
sensitivity.
2012
NCT02774993. No results available, accessed on Sept 4,
NA
100 mg qd 2012
2017
Type II diabetes
Pulmonary Tuberculosis
Phase III
Phase II
100 mg bid or placebo
100 mg bid or placebo
et
al.,
Journal Pre-proof 2019. Rebimastat
Mercaptoacyl,
2004
(BMS-275291)
thiol zinc-binding
mg qd due to free of sheddase inhibition and no arthritis
group
occurred. 2004
Advanced cancer
Phase I
Early stage breast cancer
Phase II
600 to 2,400 mg qd.
(Stage I (T1c) to IIIA)
Conventional
2004
NSCLC in stage IIIB or IV
Phase II
without chemotherapy
Good tolerability. No tumor responses. Recommend 1,200
therapy
with
High dropout rates due to adverse effects forced the clinical
BMS-275291 1,200 mg qd or placebo
trial to terminate early.
Paclitaxel
with
Well tolerated. The overall response rate of BMS-275291
BMS-275291 1,200 mg qd or placebo
arm was lower than that of the placebo arm (21.9% versus
+
carboplatin
2005
NSCLC in stage IIIB or IV
Phase III
without chemotherapy
Paclitaxel
S-3304
Sulfonamide
2005
Health male volunteer
Phase I
AZD1236
Non-hydroxamate
Neovastat
Mixed
(AE-941)
from
extract
Advanced solid tumors
n r u
Moderate to severe COPD
2012
Moderate to severe COPD
2003
shark
o J
Lung cancer
Phase II
Phase II
Phase I/II
with
Higher hypersensitivity and febrile neutropenia rates, but
BMS-275291 1,200 mg qd or placebo
no difference in MSS. No improved survival in advanced
al
Phase I
2011
carboplatin
p e
r P
10-800 mg bid versus placebo
derivatives 2007
+
f o
ro
36.4%).
800-3200 mg bid
Rizvi et al., 2004
Miller et al., 2004
Douillard et al., 2004
Leighl et al., 2005
NSCLC. Good tolerability. Good systemic exposure and free of MSS
Van Marle et al., 2005
at 800 mg bid. Good tolerability at 3200 mg bid. MMP was inhibited at
Chiappori et al., 2007
lower dose.
75 mg bid or placebo
Good tolerability. No significant treatment effects.
75 mg bid or placebo
The rates of adverse events were similar. No clinical
Magnussen
et
2011 Dahl et al., 2012
efficacy was observed. 30 to 240 mL/day bid
Good tolerability. No tumor responses were observed, but a
Latreille et al., 2003
dose-dependent increase in median survival time was
cartilage
found. 2002
Renal cell carcinoma
Phase II
60 mL/day bid or 240 mL/day bid
Good tolerability. 240 mL/day bid increased the median
Batist et al., 2002
survival time. 2010
NSCLC in stage III
Phase III
al.,
Chemotherapy with 120 mL/day bid
Good tolerability. No difference in overall survival, TDP
or placebo
and tumor response.
Lu et al., 2010
Journal Pre-proof
Clinical trials resumed after nearly ten years of trials and tribulations
FP-025
Non-hydroxamate
2017
Healthy male subjects
Phase I
50 to 800 mg qd
NCT02238834. No results available, accessed Sept 4,
f o
2019.
GS-5745
mAb inhibitor
2019
Allergic asthma
Phase II
400 mg bid or placebo
2015
Advanced solid tumors
Phase I
(Andecaliximab)
2016
2018
2018
Active ulcerative colitis
Rheumatoid arthritis
Active Crohn’s disease
NA
1,800 mg IV, followed by 800 mg IV
Manageable safety profile for GS-5745 alone or in
Bendell et al., 2015
with chemotherapy
combination with chemotherapy. More subjects need to be
o r p
e
enrolled.
Either IV infusions (0.3 to 5.0 mg/kg
Good tolerability and no MSS
or placebo) every two weeks; or five
endoscopic and histological responses were positive. The
weekly SC injections (150 mg or
dose 1 mg/kg IV, 2.5 mg/kg IV and 150 mg SC were
placebo)
recommended.
r P
al
Clinical,
n r u
3 times.
hypersensitivity (13.3%).
800 mg GS-5745 + mFOLFOX6 IV
The treatment showed encouraging clinical activity without
every two weeks
additional toxicity, especially in first-line patients with an
Phase II
150 mg SC weekly, 300 mg SC
Good tolerability. No treatment effects were observed after
weekly, 150 mg SC every two weeks,
8 weeks.
Phase I
The highest
reported.
Good tolerability.
o J
Phase I
NCT03858686. Under recruiting, accessed Sept 4, 2019.
400 mg IV every two weeks for total
Gastric/gastroesophageal junction adenocarcinoma
2018
Phase I
NA
adverse event
was
Sandborn et al., 2016
Gossage et al., 2018
Shah et al., 2018
overall response rate at 50%. Schreiber et al., 2018
and placebo 2018
2016
Ulcerative colitis
Gastric/gastroesophageal
Phase
150 mg SC weekly, 150 mg SC every
Good tolerability. Terminated at 8 weeks because of lack of
II/III
two weeks
efficacy.
Phase III
800 mg GS-5745 + mFOLFOX6 IV
NCT02545504. No results available, accessed Sept 4,
every two weeks or placebo
2019.
Various
NCT03631836. Has no recruit yet, accessed Sept 4, 2019.
junction adenocarcinoma 2019
Recurrent glioblastoma
Phase I
doses
of GS-5745 with
Sandborn et al., 2018
Bendell et al., 2016
NA
Journal Pre-proof Bevacizumab 2019
Gastric/gastroesophageal
Phase II
junction adenocarcinoma
Nivolumab + GS-5745 800 mg IV
NCT02864381. Has no recruit yet, accessed Sept 4, 2019.
NA
every two weeks or Nivolumab alone
*Abbreviations: qd once daily; bid twice daily; tid three times daily; TDP time to disease progression; SCLC small-cell lung cancer; NSCL C non-small-cell lung cancer; MSS musculoskeletal syndrome; COPD chronic obstructive pulmonary disease; mAb monoclonal antibody; IV intravenous injection; SC subcutaneous administration
f o
l a n
J
r u o
r P
e
o r p
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The hemopexin domain has a four-blade propeller structure, which is linked to the catalytic domain via a flexible hinge (Fig. 1) (Cha et al., 2002). Research have demonstrated that the hemopexin domain and the catalytic domain are conformationally independent from each other. However, during substrate recognition and collagen hydrolysis, the hemopexin domain can move relative to the catalytic domain and allosterically manipulate enzymatic
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activity (Bertini et al., 2008; Jozic et al., 2005; Overall and Butler, 2007). The term “allostery”
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here refers to the effect exerted by the distal structures, which regulate enzyme activity by
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conformational deformation (Sela-Passwell et al., 2010). The predominant advantage of
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allosteric drugs is that they provide non-competitive inhibition compared with traditional
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orthosteric compounds through the flexible dynamics of protein structure (Lu et al., 2014; Mitternacht and Berezovsky, 2011). This feature enables an allosteric inhibitor to be free
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from competition with the well-conserved catalytic site, with the advantage of avoiding
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off-target inhibition and preventing the occurrence of clinical side effects (Guarnera and
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Berezovsky, 2016). For MMPs, the long hinge is the prerequisite for flexible movement of the hemopexin domain. This long hinge regulates various functions of MMPs, including zymogen activation, oligomerization, substrate hydrolysis and inhibition through allosteric control (Sela-Passwell et al., 2010). Accordingly, targeting the hemopexin domain has been perceived as an effective means for designing selective inhibitors. For example, Remacle et al. (2012) reported a small molecule NSC405020 from the library of the DTP National Cancer Institute, which binds selectively to the hemopexin domain of MMP-14. This small molecule inhibits homodimerization of MMP-14 and the interaction between the hemopexin domain with the catalytic domain, thereby preventing degradation of type I collagen and halting
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tumor growth. Apart from allosteric control, exosites provide another alternative for selective MMPIs design. The term “exosite” is a relative concept for the catalytic site, which refers to the alternative binding site in MMP structures (Lauer-Fields et al., 2008). The major difference between allosteric sites and exosites is that the former communicates with the catalytic site
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through a dynamic conformational change, whereas the latter encompasses a much broader
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concept. To date, several exosites have been identified, including the hemopexin domain,
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collagen binding domain and pro-peptide domain (Overall, 2002); their corresponding
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selective inhibitors had been designed. For example, Dufour et al. (2010) developed a
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structure-based inhibitory peptide targeting the MMP-9 hemopexin domain, which efficiently blocks MMP-9 dimer formation and cell migration. Xu et al. (2007) synthesized a peptide
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targeting the collagen binding domain of MMP-2, which inhibits hydrolysis of type I and
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type IV collagen. Scannevin et al. (2017) identified a highly-selective compound named
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JNJ0966, which binds to the pro-peptide domain of MMP-9 and inhibits activation of pro-MMP-9 without affecting MMP-1, -2 and -14. Because the binding affinity of most exosites for substrates is typically low (10 -6 - 10-7 M), the IC50 of exosite inhibitors is in the micromolar range. Hence, exosite inhibitors do not manifest outstanding superiority over the allosteric inhibitors (Overall and Kleifeld, 2006a; Scannevin et al., 2017; Xu et al., 2007). It has been suggested recently that each MMP possesses its unique exosites or “hotspots” that may be targeted individually due to difference in their amino acid composition and diversity in geometry (Levin et al., 2017). In the future, highly-selective MMPIs may be synthesized via the combined inhibition of both the active
Journal Pre-proof site and the MMP-specific “hotspots”.
3. On-going research techniques Progress in medicine is always accompanied by technological innovation and knowledge extension. The aforementioned four generations of MMPIs are vivid examples of progressive cognitive advancement, with the inhibition target expanding from the limited small zinc
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binding site to full- length MMP structures. From a technological perspective, however, there has been little advancement on MMPI development, as they were mainly small molecules or
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peptides selected from biochemical or biophysical libraries that lacked direct synthesis based
which have greatly improved MMPI design,
namely
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two on- going techniques,
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on specific “hotspots” (Rouanet-Mehouas et al., 2016). In the following part of the review,
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antibody-based inhibitors and protein-engineering inhibitors, will be presented (Fig. 4).
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3.1 Antibody-based inhibitors
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Antibody, also known as immunoglobulin, is a large Y-shaped protein which binds to an antigen via the Fab variable region (Litman et al., 1993). Monoclonal antibodies (mAb) are antibodies that are produced by identical immune cells that are all clones of a unique parent cell. For almost any substance, it is possible to produce the corresponding mAb via phage display, single B cell culture, single-cell amplification and single plasma cell interrogation technologies. These techniques provide useful and importa nt tools in biochemistry, pharmacy and molecular biology investigations. To date, several mAbs directed against MMPs have been developed, with outstanding selectivity. One of the first MMP-9 antibodies reported was REGA-3G12, a highly-selective
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antibody against MMP-9, but not MMP-2 (Paemen et al., 1995). REGA-3G12 specifically targets the N-terminal region (Trp116 - Lys214 ) of the catalytic domain of MMP-9, but not the catalytic zinc ion or the collagen binding domain (Martens et al., 2007). DX-2400 is an antibody
isolated
from a phage display
library.
It targets MMP-14
and
the
MMP-14-dependent proMMP-2 processing, decreasing MMP activity up to 70% in animal models (Devy et al., 2009). Unlike DX-2400, the antibody LEM-2/15 only selectively inhibits MMP-14 catalytic activity toward gelatin and collagen type I without affecting
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proMMP-2 activation and MT1-MMP dimerization (Udi et al., 2015). Another antibody of MMP-14, named 9E8, has no effect on MMP-14 hydrolysis, but inhibits proMMP-2 activation (Shiryaev et al., 2013). Although DX-2400, LEM-2/15 and 9E8 are all selective MMP-14 antibody inhibitors, subtle differences exist in their regulation of downstream functions (Winer et al., 2018).
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Fig. 4 The evolution of MMP inhibitors. Cognitive advancement (blue line) and technique innovation
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(orange line) are two pillars that support the progression of MMPIs. They not only move forward
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individually, but also synergistically create the first to fourth generation of MMPIs (represented by red dots)
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and the potential future generations by their convergence. The rationale of the four generations of MMPIs
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are manifested by four representative pictures (A-D) respectively, and their features are listed on the right. In the close-up views, the catalytic zinc ion is portrayed as a green sphere; the active site His are portrayed
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as sticks in blue and white; and the zinc ion interactions are represented by purple dash lines. (A) MMP-13
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complexed to a hydroxamate-based inhibitor (PDB code: 2D1N, two chelating linkages are formed
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between Zinc ion and inhibitor). (B) A carboxylic acid inhibitor in complex with MMP-3 (PDB code: 1HY7, one chelating linkage is formed between Zinc ion and inhibitor). (C) Crystal str ucture of the complex between MMP-8 and an inhibitor enters into S 1 ’ pocket (PDB code: 3DPE, no chelating linkage is formed between Zinc ion and inhibitor). (D) Structure of a selective antibody inhibitor (GS-5745) bound to MMP-9 (PDB code: 5TH9, targeting at exosites other than catalytic domain). PDB: Protein Data Bank.
Another MMP-9 monoclonal antibody, GS-5745, is a highly-selective antibody (IC 50 = 0.148 nM) targeting four residues (R162, E111, D113, and I198) near the catalytic zinc ion. GS-5745 exerts allosteric control over tumor growth and metastasis in a colorectal carcinoma
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model (Marshall et al., 2015). To the best of our knowledge, GS-5745 (Andecaliximab) is the only mAb inhibitor that has undergone clinical trials (Table 1). A Phase I trial results suggest that GS-5745 is well tolerated by patients with ulcerative colitis and produces positive clinical, endoscopic and histological outcomes (Sandborn et al., 2016). Another Phase I trial examined the effect of GS-5745 in combination with modified-FOLFOX6 (5- fluorouracil,
f
leucovorin and oxaliplatin) in human subjects with advanced gastric /gastroesophageal
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junction adenocarcinoma. The GS-5745 treatment achieved target engagement with no
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dose-limiting toxicity, with tuning down of collagen neoepitope levels (MMP-9) that
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suggested a therapy-related effect (Shah et al., 2018). The positive results of this Phase I trial
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led to the implementation of a Phase III trial which is currently being conducted with the same treatment on the same disease with a larger anticipated population (NCT02545504,
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accessed Sept 4, 2019) (Bendell et al., 2016). Except for these ongoing clinical trials, more
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GS-5745 trials are now recruiting volunteers to explore its potential effects in different
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diseases (NCT03631836 and NCT02864381, accessed Sept 4, 2019). Despite the promising effect of antibody-based MMPIs, there are still problems that need to be addressed. For example, binding sites of antibodies are in a planar or concave shape, which do not fit well with the active sites of MMPs (pocket shape) (Levin et al., 2017). To solve this problem, Sircar et al. (2011) suggested replacing the human antibody H3 with the camelid antibody CDR-H3, which is a much longer convex-shaped paratope. After synthesizing a library of CDR-H3 modified antibodies, Nam et al. (2016) evaluated the inhibitory potency of targeting the catalytic domain of MMP-14. The results turned out to be overwhelmingly positive (IC 50 = 9.7 nM), and the hybrid antibody showed higher selectivity
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toward MMP-14 compared with MMP-2 or MMP-9. Despite these positive results, more research is needed to evaluate the biosafety and reproducibility in vivo. Apart from the shape fitness problem, the use of antibodies is limited to intravenous or subcutaneous administration, rather than oral administration, which strictly restricts its application (Vandenbroucke and Libert, 2014). Further studies are required to ameliorate antibody usage
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in a more friendly and convenient way.
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3.2 Protein-engineered inhibitors
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Protein-engineering technologies, including computational design and directed evolution,
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have been reported to be effective and valuable methods in generating desired proteins with
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novel biologic functions (Chao et al., 2006; Levin et al., 2013). Computational design facilitates the exploration of an astronomical number of protein sequences in silico to screen
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optimal protein binders, which are then experimentally verified by site-directed mutagenesis
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(Mohan et al., 2016). Directed evolution, which is based on gene mutant libraries, screens the
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desired proteins using high-throughput technology and display systems (phage, bacterial, yeast, etc.) by directed force (Banta et al., 2013). With the combination of these two methods, the protein-engineering technique appears to be the optimal technology for screening highly-selective MMPIs in an economic and efficient manner (Gebauer and Skerra, 2009). The most popular group of MMPIs derived from protein-engineering is a family of engineering N-terminal TIMPs. As previously discussed, there are four endogenous TIMPs (TIMP1-4) in the human body that form a 1:1 complex with MMP in the catalytic domain using their N-terminus peptide non-selectively (Maskos and Bode, 2003). The isolated N-TIMP is a stable peptide that retains inhibitory ability against various MMPs (Murphy et
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al., 1991). Because of their relatively small sizes, N-TIMPs may be generated via microbial cultures to create potent inhibitors for direct delivery into cancer cells (Mohan et al., 2016). Accordingly, N-TIMPs have been perceived as convenient backbones for protein-engineering to increase MMP selectivity. Harnessing on the favorable reports that binding affinity increases up to 10- fold with
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only one site mutation of the N-TIMP (Grossman et al., 2010; Nagase and Brew, 2002;
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Sharabi et al., 2014), Wei et al. (2003) increased the mutant sites to three
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(Thr2Ser/Val4Ala/Ser68Tyr) and reported that N-TIMP-1 binds to MMP-3 with picomolar
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affinity. With the help of computational design, Arkadash et al. (2017) screened 7 potential
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positions in N-TIMP-2 that may augment binding affinity. With 20 amino acids present in seven positions, a mutant library comprising over 1.3 × 109 combinations is generated. Using evolution
and
yeast
surface
display,
N-TIMP-2
with
five
mutations
al
directed
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(Ile35Met/Asn38Asp/Ser68Asn/Val71Gly/His97Arg) has been shown to be the mo st potent
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inhibitor against MMP-14 (Ki = 0.9 pM).
4. Future prospects of next generation of MMPIs The past decade was a relatively repressive time for the development of MMPIs. Almost no clinical trial was conducted, and increasing doubts have been raised on the feasibility of MMPIs in treating the associated diseases. With the development of X-ray crystallography, nuclear magnetic resonance spectroscopy, high-throughput screening and computational methods, the full- length structures of MMPs are gradually recognized. The S’ pocket, allosteric sites, and exosites brought new innovation to MMPI design. The interaction
Journal Pre-proof between monoclonal antibody with unique “hotspots” and the protein engineering technique provide efficient tools for direct protein synthesis and screening. Phase I clinical trial for GS-5745 had been successfully implemented and Phase III trial is currently being conducted after an intellectual vacuum for almost 10 years (Bendell et al., 2016). All these events have created a new era for MMP inhibitors (Fig. 5). In the following section, we provide possible
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future directions based on our own perceptions.
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4.1 Enhancing binding site specificity
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The combination of different inhibition sites and different technologies has been perceived as the most feasible way to increase the selectivity of MMPIs. Udi et al. (2013) proposed the notion of the existence of a unique region in individual MMPs that manifests the highest binding energy for ligand binding. These regions are potential selective “hotspots”
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for drug design. Because of technological limitations, the authors had to synthesize a series of
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polymers with different degrees of branching to screen the most selective entity through time-consuming experiments. With the advent of protein engineering techniques, one can now build a mutant library based on the unique amino acids held by different MMPs in silico, and screen the highly potent selective inhibitors by computational simulation (Arkadash et al.,
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2017). The early MMPIs were small molecules or peptides that could only target one binding
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site, or extended to the nearby side pockets at most. With understanding of the hotspots of each MMP, macromolecular proteins, which inhibit the catalytic site as well as specific hotspots simultaneously, may be the future goal for protein engineering techniques. 4.2 Smart drug delivery systems for achieving selectivity
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Apart from MMP binding site specificity, smart drug delivery systems, which directly
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target the designated position of MMP inhibition, are another important method to reduce off-target side effects. Matrix metalloproteinases play important roles in tumor-associated processes such as metastasis, tumor growth, angiogenesis, apoptosis and immune modulation (Fingleton, 2006). Upregulation of MMPs have been found to be positively-correlated with the development of cancer (Egeblad and Werb, 2002). For example, in benign ovarian tissues, the MMP-2 concentration is around 0.47 μg/mg, whereas the value increases to 0.78-1.2
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f
μg/mg in ovarian cancer patients, depending on the cancer stage (Schmalfeldt et al., 2001;
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Zucker et al., 1992). Hence, representative MMPs in specific diseases may be utilized as
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therapeutic targets for MMP-responsive “smart” drug delivery systems (Yao et al., 2018).
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Currently, three MMP-responsive drug release methods have been proposed, namely, linker cleavage, structure disassembly and membrane “uncorking” (Yao et al., 2018). In these three
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methods, the drug molecules are either conjugated to the polymer via an MMP-sensitive
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linker, or encapsulated in a degradable nanoparticle or opened by a specific MMP. By using
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the linker cleavage and membrane “uncorking” methods, Purcell et al. (2014) synthesized an injectable and bioresponsive MMP-sensitive hydrogel containing a recombinant tissue inhibitor of MMPs (rTIMP-3) (Purcell et al., 2014). This hydrogel/rTIMP-3 system produces minimal release in non-targeted tissues (that is, lack of MMP activity) and significantly suspends tissue remodeling in myocardial infarction. Further steps may be implemented, such as encapsulating highly-selective mAb inhibitors within MMP-responsive nanoparticles. Such a strategy may change the drug delivery method from parenteral injection to more patient-friendly oral administration without adversely affecting the function of mAb inhibitors.
Journal Pre-proof Fig 5. Timeline listing milestones in the discovery, design and development of MMPIs
4.3 Thorough understanding of MMPs in health and disease A thorough understanding of the functions of different MMPs in different diseases under different spatiotemporal conditions should be the ultimate goal for scientists in this research
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arena. Numerous reports have indicated that MMPs play different roles in different biological systems, such as substrate recognition, signal transmission and protein-protein interactions.
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These substrates and signal molecules together with MMPs form a dynamic web – the
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“protease web”, which entangle with each other and maintain homeostasis in a subtle balance
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(Overall and Kleifeld, 2006b). Subsequently, a single MMP can degrade/activate different
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substrates that may exert opposite effects on physiologic function or disease progression. As
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mentioned previously, the three different mAb inhibitors (DX-2400, LEM-2/15 and 9E8) all
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target at MMP-14 selectively, but their downstream substrates vary from each other (Devy et al., 2009; Shiryaev et al., 2013; Udi et al., 2015). The latest MMP research opens new views in the understanding of previously unrecognized cell physiology. Working with the neamtode C. elegans, Kelley et al. (2019) demonstrated that in the absence of MMPs, invasive cancerous cells can still penetrate the basement membrane via an alternative method. This is achieved via the formation of F-actin-rich protrusions that physically breach and displace the basement membrane (albeit much slower than MMP- mediated degradation). If such a biological process really occurs in human cells, the theory on prevention of cancer metastasis via MMP inhibition will no longer
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be valid (Castro-Castro et al., 2016; Kessenbrock et al., 2015). Although the role of MMPs in cancer metastasis may be mellowed, their regulation on other aspects of cancer progression, as well as the whole “protease web” should not be overlooked. A subtle shift of emphasis from direct blocking of MMPs to targeting the MMP substrate and “after metastasis” processes may be the future direction for developing new generations of MMPIs. This latest
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research emphasizes that sophisticated and complex cellular pathways mediated by different
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MMPs in different diseases need to be further understood. In addition, specific signal
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peptides and structure binding sites need to be further characterized, and well-designed
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clinical trials need to be further implemented in order for MMP-strategized therapeutics to be
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successful.
5. Concluding remarks
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It has been nearly five decades since the discovery of MMP in tadpoles. Since then, the
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progress in deciphering the roles of MMPs in human physiologic functioning and disease
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progression has been nothing short of phenomenal. Although a plethora of reviews on MMP inhibitors have recently been published and provided insights on future development of MMP inhibitors (Fields, 2019a; Fischer and Riedl, 2019; Fields, 2019b; Young et al., 2019; Fischer et al., 2019; Cerofolini et al., 2019), this review is original in the following aspects: (1) the historical development of MMPIs was described under two perspectives, cognitive advancement and technique innovations so that the characteristics of different MMPIs and the reasoning behind the supersession could be easily understood; (2) In the previous reviews, the MMPIs were only defined up to the third generation, the catalytic domain inhibitors. In the current review, the fourth generation MMPIs, the allosteric control and exosit es control
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inhibitors, were described and added to cover the full spectrum of MMPIs; (3) Apart from the synthesized MMPIs, the natural MMPIs derived from plants and marine environments were also included; their pros and cons were discussed; (4) After almos t 10 years of intellectual vacuum, the Phase I clinical trial of newly antibody-based inhibitors had been successfully implemented and Phase III trial is currently being conducted. These novel clinical trials have
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brought new hope for future developments of MMPIs and they have been summarized along
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with previous clinical trials in the current review. Although research on MMP inhibitors was
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not as successful as anticipated, the fruits derived from previous studies are invaluable for
should
be
cautiously
optimistic
that
structurally-selective
and
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profession
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shaping future research. With the development of new experimental techniques, the
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spatiotemporally-specific MMPIs with minor off-targeting effects will blossom.
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Conflict of Interest Statement
References
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The authors declare that there are no conflicts of interest.
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Sela-Passwell, N., Rosenblum, G., Shoham, T., & Sagi, I. (2010). Structural and functional bases for allosteric control of MMP activities: can it pave the path for selective inhibition? Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1803, 29-38. Shah, M . A., Starodub, A., Sharma, S., Berlin, J., Patel, M ., Wainberg, Z. A., Chaves, J., Gordon, M ., Windsor, K., & Brachmann, C. B. (2018). Andecaliximab/GS-5745 alone and combined with mFOLFOX6 in advanced gastric and gastroesophageal junction adenocarcinoma: results from a phase I study. Clinical Cancer Research, 24, 3829-3837. Sharabi, O., Shirian, J., Grossman, M ., Lebendiker, M ., Sagi, I., & Shifman, J. (2014). Affinity -and specificity-enhancing mutations are frequent in multispecific interactions between TIM P2 and M M Ps. PloS One, 9, e93712. Shiryaev, S., Remacle, A., Golubkov, V., Ingvarsen, S., Porse, A., Behrendt, N., Cieplak, P., & Strongin, A. (2013). A
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Terp, G. E., Cruciani, G., Christensen, I. T., & Jørgensen, F. S. (2002). Structural differences of matrix metalloproteinases with potential implications for inhibitor selectivity examined by the GRID/CPCA approach. Journal of Medicinal Chemistry, 45, 2675-2684.
Udi, Y., Fragai, M ., Grossman, M ., M itternacht, S., Arad-Yellin, R., Calderone, V., M elikian, M ., Toccafondi, M ., Berezovsky, I. N., & Luchinat, C. (2013). Unraveling hidden regulatory sites in structurally homologous metalloproteases. Journal of Molecular Biology, 425, 2330-2346. Udi, Y., Grossman, M ., Solomonov, I., Dym, O., Rozenberg, H., M oreno, V., Cuniasse, P., Dive, V., Arroyo, A. G., & Sagi, I. (2015). Inhibition mechanism of membrane metalloprotease by an exosite-swiveling conformational antibody. Structure, 23, 104-115. Van M arle, S., Van Vliet, A., Sollie, F., Kambayashi, Y., & Yamada-Sawada, T. (2005). Safety, tolerability and pharmacokinetics of oral S-3304, a novel matrix metalloproteinase inhibitor, in single and multiple dose escalation studies in healthy volunteers. International Journal of Clinical Pharmacology & Therapeutics, 43. 282-293.
Journal Pre-proof Vandenbroucke, R. E., & Libert, C. (2014). Is there new hope for therapeutic matrix metalloproteinase inhibition? Nature Reviews Drug Discovery, 13, 904. Vanlaere, I., & Libert, C. (2009). M atrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock. Clinical Microbiology Reviews, 22, 224-239. Visse, R., & Nagase, H. (2003). M atrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circulation Research, 92, 827-839. Wang, L., Li, X., Zhang, S., Lu, W., Liao, S., Liu, X., Shan, L., Shen, X., Jiang, H., & Zhang, W. (2012). Natural products as a gold mine for selective matrix metalloproteinases inhibitors. Bioorganic & Medicinal Chemistry, 20, 4164-4171.
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Wei, S., Chen, Y., Chung, L., Nagase, H., & Brew, K. (2003). Protein engineering of TIM P-1 inhibitory domain: In search of selective M M P inhibitors. Journal of Biological Chemistry, 278, 9831-9834.
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Winer, A., Adams, S., & M ignatti, P. (2018). M atrix metalloproteinase inhibitors in cancer therapy: turning past failures into
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future successes. Molecular Cancer Therapeutics, 17, 1147-1155. Wojtowicz-Praga, S., Low, J., M arshall, J., Ness, E., Dickson, R., Barter, J., Sale, M ., M cCann, P., M oore, J., & Cole, A.
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Woolley, D. E., Roberts, D. R., & Evanson, J. M . (1975). Inhibition of human collagenase activity by a small molecular
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Epidemiology and Prevention Biomarkers, 1, 475-479.
future
perspectives
of
matrix
Kang Li, Franklin R. Tay, Cynthia Kar Yung Yiu PII:
S0163-7258(19)30217-7
DOI:
https://doi.org/10.1016/j.pharmthera.2019.107465
Reference:
JPT 107465
To appear in:
Pharmacology and Therapeutics
Please cite this article as: K. Li, F.R. Tay and C.K.Y. Yiu, The past, present and future perspectives of matrix metalloproteinase inhibitors, Pharmacology and Therapeutics(2019), https://doi.org/10.1016/j.pharmthera.2019.107465
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© 2019 Published by Elsevier.
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P&T 23637 The Past, Present and Future Perspectives of Matrix Metalloproteinase Inhibitors Article Type: Review Article
Kang Li1 , Franklin R. Tay2 *, Cynthia Kar Yung Yiu1 *
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1. Paediatric Dentistry and Orthodontics, Faculty of Dentistry, The University of
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Hong Kong, Prince Philip Dental Hospital, 34 Hospital Road, Sai Ying Pun, Hong
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Kong
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2. College of Graduate Studies, Augusta University, Augusta, GA, USA
Email: [email protected]; [email protected] (*co-corresponding authors)
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Tel: +852 28590256
Declaration:
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Fax: +852 25593803
The article titled “The Past, Present and Future Perspectives of Matrix Metalloproteinase Inhibitors” has not been published and is not under consideration for publication elsewhere.
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Abstract: Matrix metalloproteinases (MMPs) are a large family of enzymes that degrade the extracellular matrix (ECM). Under pathologic conditions, overexpression of MMPs or insufficient control by tissue inhibitors of MMPs (TIMPs) results in the dysregulation of tissue remodeling and causes a variety of diseases such as encephalomyelitis, rheumatoid arthritis, Alzheimer’s disease and tumors. Therefore,
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the high affinity of MMPs for biomolecules renders them attractive targets for
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inhibition when homeostasis breaks down in the ECM. There are 4 generations of
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MMP inhibitors (MMPIs), ranging from small molecules or peptides to antibodies and
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protein-engineered inhibitors of metalloproteinase. Although a plethora of MMPIs has
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been synthesized, most of them have failed in clinical trials or are still in the laboratory stage of development. The present review summarizes the development of
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MMPIs, their associated problems and discusses future directions for the development
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of the future generations of MMPIs.
Key Words: Matrix metalloproteinase; MMP; Inhibitor; MMPI
Journal Pre-proof Table of Contents: 1. Introduction 2. Historical generations of MMPIs 2.1 First generation – hydroxamate-based inhibitors 2.2 Second generation – non-hydroxamate-based inhibitors 2.3 Third generation – catalytic domain (non-zinc binding) inhibitors 2.4 Fourth generation -- allosteric and exosite inhibitors 3. On-going research techniques
3.2 Protein-engineered inhibitors
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4.1 Enhancing binding site specificity
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4. Future prospects of next generation of MMPIs
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3.1 Antibody-based inhibitors
4.2 Smart drug delivery systems for achieving selectivity
5. Concluding remarks
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References
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Conflict of interest statement
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4.3 Thorough understanding of MMPs in health and disease
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Abbreviations: ADAM, a disintegrin and metalloproteinase; ADAMTS, ADAM with thrombospondin motifs; bid, twice daily; COPD, chronic obstructive pulmonary disease; ECM, extracellular matrix; FDA, Food and Drug Administration; GPI, glycophosphatidylinositol; IV, intravenous injection; mAb, monoclonal antibody; MMP, Matrix metalloproteinase; MMPI, Matrix metalloproteinases inhibitor; MSS, musculoskeletal syndrome; MT, membrane-type; NSCLC, non-small-cell lung cancer; N-TIMP, N-terminal peptide of TIMP; PDB, Protein Data Bank; qd, once daily; SC, subcutaneous administration; SCLC, small-cell lung cancer; TDP, time to disease progression; tid, three times daily; TIMP, tissue inhibitors of MMP.
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1. Introduction Matrix metalloproteinases (MMPs) were first discovered in 1962 by Gross and Lapiere in the tail of tadpole during frog metamorphosis (Gross and Lapiere, 1962). These enzymes have been recognized as the major proteolytic enzymes for regulating extracellular matrix (ECM) degradation (Gross, 2004). To date, 23 MMPs have been
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identified in humans. Apart from their tissue-remodeling function, MMPs also
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participate in regulating many non- matrix targets, such as cell surface receptors,
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proteinases (Vanlaere and Libert, 2009).
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cell-cell adhesion molecules, cytokines, clotting factors, chemokines and other
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Matrix metalloproteinases may be classified in two different ways, based on substrate or domain organization. The substrate classification is more common and
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categories MMPs into collagenases (MMP-1, MMP-8, and MMP-13), gelatinases
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(MMP-2 and MMP-9), stromelysins (MMP-3, MMP-10, and MMP-11), matrilysins
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(MMP-7 and MMP-26), membrane-type (MT) MMPs (MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25) and others (MMP-12, MMP-19, MMP-20, MMP-21, MMP-23, MMP-27, and MMP-28) (Visse and Nagase, 2003). Many studies have pointed out the limitation of this classification. For example, MMP-1, designated as a collagenase, also cleaves tenascin and aggrecan; MMP-2, a gelatinase, also degrades fibronectin, aggrecan and non-ECM substrates. Even MMP-14, a well-known MT1-MMP, serves as a collagenase (Chakraborti et al., 2003; Tam et al., 2004). The easily misleading names and the unclassified MMPs have limited the accuracy of substrate-based classification.
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An alternative classification of MMPs has been proposed based on their domain organization. In this classification, MMPs may be divided into archetypal MMPs, matrilysins, gelatinases and furin-activable MMPs (Fanjul-Fernández et al., 2010; Vandenbroucke and Libert, 2014) (Fig. 1). All MMPs share some common domain structures (except MMP-7, MMP-23, and MMP-26). The signal peptide mediates
This intramolecular cysteine-switch keeps MMPs in their
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with a cysteine residue.
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MMP secretion. The pro-peptide protects the Zn2+ binding site through interaction
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latent, inactive pro- forms until cleavage of the pro-peptide domain. The catalytic
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domain, which contains Zn2+, is responsible for substrate hydrolysis. The hemopexin
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domain, which is linked to catalytic domain via a flexible hinge, is responsible for
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substrate recognition and dimerization (Aureli et al., 2008; Tallant et al., 2010). Fig.1 Structural classification of MMPs based on their domain arrangement and the relationship with other metzincins superfamily members
Apart from the commonly-shared structures, there are features which are characteristic of individual MMPs. These characteristics include: (1) MMP-7 and MMP-26 lack the hinge region and the hemopexin domain; (2) MMP-2 and MMP-9
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contain three fibronectin type II motifs (aka. collagen binding domain) on the catalytic site; (3) furin-activable MMPs have a furin cleavage motif between the
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pro-peptide and catalytic domain; (4) MT-MMPs have a transmembrane domain or
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glycophosphatidylinositol (GPI) anchor on their C-terminus; and (5) MMP-23 lacks
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the signal peptide, the cysteine-switch motif and the hemopexin domain. The structure of ECM is not static. Under normal conditions, MMPs and
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endogenous tissue inhibitors of MMPs (TIMPs) mutually participate in the
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homeostasis of the ECM (Overall and López-Otín, 2002; Woolley et al., 1975). The
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TIMP family consists of four members, namely TIMP1-4, which were first identified in serum and tissue culture (Bauer et al., 1975; Eisen et al., 1971). Each TIMP forms a 1:1 complex with MMP in a non-selective manner (Maskos and Bode, 2003). The three-dimensional structures
of
TIMP-MMP
complexes
stipulate
that
the
wedge-shaped ridge of the N-terminal peptide of TIMP (N-TIMP, consisting of approximately 126 amino acids) interacts with the Zn2+ of MMP active site through the α-amino and carbonyl groups. In addition, the serine/threonine group of N-TIMP interacts with the nucleophilic glutamine in the MMP catalytic site and activates the hydrolysis process (Mohan et al., 2016). Under pathologic conditions, overexpression
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of MMPs or insufficient control by TIMPs results in the dysregulation of tissue remodeling and causes a variety of diseases, such as encephalomyelitis (Mohan et al., 2016), rheumatoid arthritis (Ahrens et al., 1996), Alzheimer’s disease (Peress et al., 1995) and tumors (Coussens et al., 2002). Hence, MMPs are often considered valuable drug targets. A plethora of MMP inhibitors (MMPIs) have been designed for
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the purpose of restoring tissue homeostasis and curing diseases.
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As early as 1988, Reich et al. used a hydroxamic acid compound (SC-44463) to
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block collagenase and prevent metastasis in mouse models, which initiated the era of
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MMP inhibition therapeutics. Following that seminal study, clinical trials commenced
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with great enthusiasm and expectations on the first generation MMPIs (such as Batimastat, Marimastat, MMI-270 and Prinomastat) (Table 1). However, after nearly
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30 years of trials and tribulations, only one drug (Periostat®, doxycycline hydrate) had
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obtained approval from the US Food and Drug Administration (FDA) for the
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treatment of periodontal disease (Golub et al., 2001; Preshaw et al., 2004; Wynn, 1999). Accordingly, the objective of the present review is to provide a summary of the historical generations of MMPIs as well as the lessons acquired from those developments. This is followed by reviewing the latest research directions on MMPI synthesis, and finally, perspectives on the development of future generations of MMPIs.
2. Historical generations of MMPIs 2.1 First generation – hydroxamate-based inhibitors
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The first generation MMPIs are mainly small molecules or peptides containing the hydroxamate zinc-binding group (-CONHOH), which shows strong interaction with the Zn2+ ion on the catalytic domain of MMPs (Whittaker et al., 1999). The active
site
of
all
MMPs
shares
a
highly-conserved
sequence
motif
(His-Glu-Xxx-Gly-His-Xxx-Xxx-Gly-Xxx-Xxx-His). Because the three histidine
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residues form coordinate bonds with the catalytic Zn2+ ion, the hydroxamate group
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has the capability of inhibiting a broad-spectrum of MMPs (Bode et al., 1999). For
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example, Batimastat, the first MMPI to enter clinical trials for cancer, inhibits MMP-1,
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-2, -7, and -9 (Wojtowicz-Praga et al., 1996). However, due to its poor oral
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bioavailability, Batimastat was superseded by Marimastat, which retained the property of its predecessor, but manifested better oral bioavailability (Nemunaitis et al., 1998).
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Prinomastat, another hydroxamate-based inhibitor, shows high affinity toward
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MMP-2, -3, -9, -13, and -14 over MMP-1 (Hande et al., 2004).
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Although animal-derived pre-clinical results of these hydroxamate-based inhibitors were fairly promising (Davies et al., 1993; Giavazzi et al., 1998), all subsequent clinical trials failed because of several reasons. Firstly, severe side effects such as musculoskeletal syndrome (MSS) and inflammation occurred in patients, which were not observed in the pre-clinical models (Skiles et al., 2004). These side effects were probably attributed to the broad-spectrum inhibiting property of the hydroxamate group. This group also inhibits the ADAMs (a disintegrin and metalloproteinase) family and ADAMTSs (ADAMs with thrombospondin motifs) family, two large related families of MMPs (Fig. 1), which play important roles in
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cellular regulation, cell- matrix interactions and membrane protein shedding (de Arao Tan et al., 2013; Edwards et al., 2008). Secondly, cancer patients who enrolled in the clinical trials were mostly at the advanced stage of the disease. By contrast, animal models that are utilized in the pre-clinical studies manifested only the early stage of cancer. While MMPs produced by stromal cells are important during the early aspects
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of cancer progression (i.e. local invasion), they may no longer be required once
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metastases have been established (Zucker et al., 2000). Thirdly, hydroxamate-based
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inhibitors were labile and unstable; their rapid clearance rate and short half- lives
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hindered their clinical application (Peng et al., 1999).
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2.2 Second generation – non-hydroxamate-based inhibitors
Fig. 2 Schematic representation of four zinc-binding groups (a: hydro xamate, b: thiolate, c: carbo xylate, and d: phosphinate) in complex with the zinc ion
To solve the problems associated with first generation MMPIs, the pharmaceutical industry began to shift its attention to non- hydroxamate-based inhibitors such as thiolate, carboxylate and phosphinate (Fig. 2) (Devel et al., 2010).
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The most significant difference between non-hydroxamate-based inhibitors and hydroxamate-based inhibitors is their affinity for the catalytic Zn2+ ion. The hydroxamate is a strong Zn2+-chelating group, which anchors itself tightly to the Zn2+ ion. This strong anchoring mechanism hinders the free orientation of the rest of the compound. On the contrary, the non-hydroxamate group is a relatively weak
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Zn2+-chelating group. Although there is some reduction of the inhibitor ’s potenc y, this
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weak binding property reduces off-target binding to the ADAMs and ADAMTSs
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families, thereby preventing side effects to a certain extent (Skiles et al., 2001). As
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reported by Overall and Kleifeld (2006a), introduction of the hypophosphite group
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increased the selectivity towards MMP-1 (Ki = 5 nM), compared with MMP-7 (Ki = 78 nM) by one order of magnitude. Likewise, introduction of the carboxylate group
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increased MMP selectivity by two orders of magnitude (Ki = 2 nM for MMP-1 and Ki
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= 850 nM for MMP-7). Despite these improvements, it is now well accepted that an
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ideal MMP-selective inhibitor should increase the difference in Ki over targets by three log orders. This is difficult to achieve in the catalytic zinc sites because of their highly homogeneous sequences (Overall and Kleifeld, 2006a). Clinical results conducted on non- hydroxamate-based inhibitors were mixed with success and failure. Because of their weak Zn2+-chelating ability, the rates of severe MSS decreased dramatically compared with the hydroxamate-based inhibitors. Although this was extremely encouraging, the invalid and even negative treatment effects of most non- hydroxamate-based inhibitors (except doxycycline) still casted a shadow on the ongoing and future clinical trials (Table 1). For example, Tanomastat,
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which contains a thioether zinc-binding group, had no serious MSS reported, but efficacy was invalid and even negative results were detected compared with the placebo arm in small-cell lung cancer patients (Erlichman et al., 2001; Hirte et al., 2006; Moore et al., 2003; Rigas et al., 2003). Metastat (COL-3), a tetracycline derivative inhibitor, had contradictory treatment effects in different diseases, and the
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high rates of photosensitivity reaction despite fastidious sun protection hindered the
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enthusiasm for pharmaceutical companies to proceed to Phase III trials (Chu et al.,
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2007; Cianfrocca et al., 2002; Rudek et al., 2001). Rebimastat (BMS-275291)
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(Douillard et al., 2004; Leighl et al., 2005; Miller et al., 2004; Rizvi et al., 2004),
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S-3304 (Chiappori et al., 2007; Van Marle et al., 2005) and AZD1236 (Dahl et al., 2012; Magnussen et al., 2011) all showed good tolerability, but no improved survival
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and convincing treatment effects were observed (Table 1).
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Setting all these failures aside, the only MMPI which gave people relief was
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doxycycline. As mentioned above, the Periostat® (doxycycline at sub-antimicrobial dose - 20 mg twice daily) is the only MMPI approved by FDA to date. Except for its outstanding performance in treating periodontitis, doxycycline at different dose levels also exhibited acceptable therapeutic effects in treating aortic aneurysms, multiple sclerosis as well as type II diabetes (Baxter et al., 2002; Frankwich et al., 2012; Minagar et al., 2008). Further Phase III trials are needed in larger populations to provide stronger evidence.
2.3 Third generation – catalytic domain (non-zinc binding) inhibitors Learning from the limitations of the former two generations of MMPIs, scientists
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began to shy away from the scope of the zinc binding group and target the catalytic domain of MMPs instead. In addition to the zinc binding site, the catalytic domain contains many other recognition pockets, half of which are on the r ight side of the Zn2+ ion (called primed side, with pockets named S 1 ’, S2 ’, S3 ’) and the other half on the left side (called unprimed side, with pockets named S 1 , S2 , S3 ) (Fig. 3a). The part of substrates or inhibitors that can fit into the S n pocket is named Pn accordingly (for
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example, P1 ’ fits in S1 ’, P2 fits in S2 ) (Whittaker et al., 1999). Among these
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recognition pockets, S1 ’ varies the most among different MMPs in the amino acid
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sequence and pocket depth. Consequently, the ranking of the selectivity of the
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recognition pockets toward substrates or inhibitors are: S1 ’ > S2 , S3 , S3 ’ > S1 > S2 ’ (Aureli et al., 2008; Pirard, 2007). Based on the depth of S1 ’ pocket or S1 ’ cavity (Fig.
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3c), MMPs may be separated into shallow (MMP-1, -7), intermediate (MMP-2, -8, -9),
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and deep pocket (MMP-3, -11, -12, -13, -14) (Aureli et al., 2008; Jacobsen et al., 2010;
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Park et al., 2003). The difference has been utilized in developing selective MMPIs. For example, inhibitors with a long P 1 ’ substituent like aromatic groups can fit in the large deep pocket of MMP-3, but are not accessible to MMP-1 and -7 because of their limited pocket depth (Terp et al., 2002). This method increased the selectivity to some extent; however, the intermediate and other similar deep pocket MMPs cannot be distinguished by simply elongating the P1 ’ substituent. With the development of X-ray crystallography, nuclear magnetic resonance spectroscopy, high-throughput screening and computational methods, structural differences in the S1 ’ pocket depth have been gradually recognized. A variety of
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highly-selective MMPIs with up to three orders of magnitude inhibition capacity have been developed (Matter and Schudok, 2004; Overall and Kleifeld, 2006a; Rao, 2005). For example, Pochetti et al. (2009) reported a selective inhibitor of MMP-8, which
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Pr
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induces a conformational change of the S 1 ’ loop (Fig. 3b). This, in turn, exposed an
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Pr
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pr
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extra binding region of the pocket by switching of the Y227 side chain, thereby improving the selectivity of MMP-8 (IC50 = 7.4 nM). Engel et al. (2005) identified another selective inhibitor, the pyrimidine dicarboxamide, which not only binds to the deep S1 ’ pocket of MMP-13, but also protrudes into a side pocket of S 1 ’, a feature that
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has not been observed in other MMPs (Fig. 3d). This observation led to an improved IC50 of 8 nM toward MMP-13 and against MMP-1, -2, -3, -7, -8, -9, -10, -12, -14, and -16 (IC50 > 100 μM). Inspired by the work of Engel et al. (2005), Gege et al. (2012) synthesized a highly-selective MMP-13 inhibitor with IC 50 = 0.03 nM, which is 20,000-fold over other MMPs.
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Fig. 3 Representation of the X-ray structure of MMP catalytic domain. The Zn 2+ appears as a
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purple dot. (a) The general location of S 3 -S3 ’ pockets indicated by circles (PDB code: 2OY4,
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uninhibited human MMP-8). (b) The indication of S 1 ’ loop, which is conformational flexible (PDB
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code: 3DPE, the complex between MMP-8 and a non-zinc chelating inhibitor). (c) The inhibitor is
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highlighted to indicate the S 1 ’ pocket depth (PDB code: 3DPE, the complex between MMP-8 and a non-zinc chelating inhibitor). (d) The inhibitor is highlighted to indicate its protrusion into S 1 ’
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Protein Data Bank.
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side pocket (PDB code: 1XUD, MMP-13 complexed with non-zinc binding inhibitor). PDB:
Apart from the synthesized MMPIs, many natural compounds have also been shown to possess selective inhibition via adaptation with specific MMP pockets. Wang et al. (2012) identified 19 potential MMPIs from 4,000 natural compounds isolated from 100 medicinal plants using structure-based virtual screening. After further testing, two classes of natural compounds (namely, caffeates and flavonoids) were found to have selective inhibition ability against MMP-2 and MMP-9 by occupying the S1 ’ and S3 pockets (Wang et al., 2012). Apart from plant-derived natural compounds, marine natural products are another huge pharmacological
Journal Pre-proof
resource that have great potential in targeting MMPs (Gentile and Liuzzi, 2017). The major MMPIs of the marine environment are derivatives from algae, sponges and cartilage, such as Neovastat, Dieckol, Ageladine A and chitin. The y all manifest anti-angiogenic, anti-proliferative and anti-tumor effects to some extent (Agrawal et al., 2018).
f
Compared with synthetic MMPIs, natural MMPIs are more bio- friendly and less toxic.
oo
However, they still have several drawbacks. Firstly, the effective dosage of most
pr
natural MMPIs lie in micromolar scale, which is thousands of times higher than the
e-
third generation synthetic MMPIs, not to mention the forthcoming protein-engineered
Pr
MMPIs which lie in the picomolar scale (Arkadash et al., 2017; Engel et al., 2005; Gege et al., 2012). Despite the reduced cytotoxicity for natural MMPIs per unit, the
al
overall side-effects on human subjects still require further evaluation via
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well-designed clinical trials. Secondly, some natural compounds that possess
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anti-MMP effects are mixtures derived from plants or the marine environment, such as the grape seed extract and Neovastat (isolated from shark cartilage). They have encountered the same challenges as with Chinese medicine, in that the effective chemical molecule cannot be defined. Consequently, even though the Phase II clinical trials were successful, the inability to set proper surrogate markers prevented the detection of potential clinical benefits in the Phase III clinical trials (Batist et al., 2002; Latreille et al., 2003; C. Lu et al., 2010). Thirdly, because it is difficult to patent these natural compounds, pharmaceutical companies and other investors are reluctant to sponsor large-scale clinical trials. Hence, data collected for potential natural MMPIs
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are inadequate to support their superiority over synthetic MMPIs.
2.4 Fourth generation -- allosteric and exosite inhibitors Apart from the catalytic domain, MMPs contain other distal structures such as the hemopexin domain, the collagen binding domain and the pro-peptide domain. Because these domains are far remote from the catalytic domain, previous research
oo
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had not devoted much attention to their behaviors. As the full- length MMP structures are gradually unveiled, the functions of these additional domains in substrate
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recognition, signal transmission as well as protein-protein interactions are gradually
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recognized. These non-catalytic domains may be further utilized in designing
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selective MMPIs (Sela-Passwell et al., 2010).
Journal Pre-proof Table 1 Summary of MMP Inhibitors Clinical Trials MMPI name Batimastat
Structure Hydroxamate
Year 1996
Disease
Stage
Malignant tumors
Phase I
Treatment
(BB-94)
600,
Marimastat
1,200,
1,800
mg/m
2
via
Results
References
Mainly local toxicities, especially abdominal discomfort.
Wojtowicz-Praga
intraperitoneal injection Hydroxamate
1998
Malignant tumors
Phase I/II
(BB-2516) 2001
Pancreatic cancer
Phase III
et
al., 1996
5 mg to 100 mg bid or 5 mg to 25 mg
MSS increased in dosage over 50 mg bid after 1 month
qd
usage. Recommend 10 and 25 mg bid.
1998
5, 10, 25 mg bid vs. gemcitabine
1-year survival rate: 25 mg = gemcitabine > 10 mg = 5 mg;
Bramhall et al., 2001
f o
ro
Nemunaitis
et
al.,
MSS: 44% of marimastat > 12% of gemcitabine. 2002
Pancreatic cancer
Phase III
2002
Gastric cancer
Phase III
Gemcitabine with 10 mg bid or
-p
placebo
2004
MMI-270
Hydroxamate
2001
Metastatic breast cancer
Advanced solid cancer
Phase III
Prinomastat
Hydroxamate
2004
J
Advanced cancer
(AG3340) 2005
2006
NSCLC (Stage IIIB or IV)
Resectable
esophagus
Phase I
Phase I
Biphenyl,
(Bay 12-9566)
thioether
2001
Solid tumor
tolerated.
al., 2002
Positive treatment effect. Severe MSS observed.
Bramhall,
No difference in treating effects. MSS was associated with
Hallissey,
et al., 2002 Sparano et al., 2004
inferior survival. Rash and MSS observed in doses ≥ 300 mg bid. No
50 mg qd to 600 mg tid
5-fluorouracil
Bramhall, Schulz, et
Levitt et al., 2001
obvious tumor response. The recommended Phase II dose was 300 mg bid. +
folinic
acid
+
Severe MSS observed in 300 mg bid. Six patients (18.2%)
MMI-270 (50 mg qd, 150 mg tid or
had a partial response and 17 patients (51.5%) had stable
300 mg bid)
disease.
1 mg to 100 mg bid
No tumor response. 5-10 mg bid were recommended for
Eatock et al., 2005
Hande et al., 2004
longer treatment. Phase III
Phase II
cancer (Stage II or higher) Tanomastat
al
rn
u o
Colorectal cancer
e r P
10 mg bid vs. placebo
Phase I
(CGS27023A)
2005
10 mg bid vs. placebo
No treatment effect; gemcitabine + marimastat was well
Phase I
Gemcitabine + cisplatin with 15 mg
Terminated early because of lack of treatment efficacy.
bid or placebo
MSS incidence increased.
5-FU + cisplatin + paclitaxel with 15
Early termination due to unexpected thromboembolic
mg bid or placebo
events. No definitive conclusions were obtained.
400 mg qd, 400 mg bid, 400 mg tid
Toxicity was mild. No MSS. No tumor responses. Due to
and 800 mg bid.
the low toxicity, 800 mg bid could be further tested.
Donald et al., 2005
Heath et al., 2006
Erlichman et al., 2001
Journal Pre-proof zinc-binding group 2003
SCLC and NSCLC
Phase III
800 mg bid vs. placebo
For NSCLC, the TDP was significantly increased.
Rigas et al., 2003
However, for SCLC, the TDP was significantly decreased. 2003
Pancreatic cancer without
Phase III
800 mg bid vs. gemcitabine
Early termination due to the poorer survival. Both arms had
prior chemotherapy 2006
Moore et al., 2003
low rates of serious toxicity.
Ovarian cancer with prior
Phase III
f o
Early termination due to Bayer’s decision. Well tolerated
800 mg bid vs. placebo
effective treatment
Hirte et al., 2006
without grade 3 or 4 adverse events, but has no positive
ro
treatment effects. Metastat
Tetracycline
(COL-3)
derivatives
2001
Refractory solid tumors
36, 50, 70, and 98 mg/m 2 qd.
Phase I
AIDS-Related
Kaposi’s
Phase I
25, 50 and 70 mg/m
sarcoma
2007
Cianfrocca
Significant change in MMP-2 levels.
2002
50 mg/m qd, and instructed to apply
Photosensitivity reaction despite fastidious sun protection.
Chu et al., 2007
sun protection procedures.
No obvious treatment effects.
20 mg bid (sub-antimicrobial dose) or
Well tolerability. Outstanding effects without causing
placebo
dysbacteriosis.
20 mg bid (sub-antimicrobial dose) or
Well
placebo
outcomes.
100 mg bid
Well tolerability. No significant change in aneurysms
r P
qd, and
instructed to apply sun protection
Advanced
soft
tissue
sarcoma 2001
Periodontitis
2004
Periodontitis
al
Phase II
n r u
derivatives
Phase II/III
2002
2
Photosensitivity reaction. Overall response rate was 44%.
procedures.
Tetracycline
p e
Rudek et al., 2001
recommended.
2002
Doxycycline
High rates of cutaneous phototoxicity. 36 mg/m2 qd was
o J
Asymptomatic abdominal
Phase III
Phase II
2
aortic aneurysms
tolerability.
Significantly
improvement
in
all
et
al.,
Golub et al., 2001
Preshaw et al., 2004
Baxter et al., 2002
diameter, but significant reduction in plasma MMP-9 level after 6 months treatment.
2008
Multiple sclerosis
Phase II
Interferon beta-1a with doxycycline
The therapy was effective, safe and well-tolerated.
Minagar et al., 2008
Doxycycline decreas ed inflammation and improved insulin
Frankwich
sensitivity.
2012
NCT02774993. No results available, accessed on Sept 4,
NA
100 mg qd 2012
2017
Type II diabetes
Pulmonary Tuberculosis
Phase III
Phase II
100 mg bid or placebo
100 mg bid or placebo
et
al.,
Journal Pre-proof 2019. Rebimastat
Mercaptoacyl,
2004
(BMS-275291)
thiol zinc-binding
mg qd due to free of sheddase inhibition and no arthritis
group
occurred. 2004
Advanced cancer
Phase I
Early stage breast cancer
Phase II
600 to 2,400 mg qd.
(Stage I (T1c) to IIIA)
Conventional
2004
NSCLC in stage IIIB or IV
Phase II
without chemotherapy
Good tolerability. No tumor responses. Recommend 1,200
therapy
with
High dropout rates due to adverse effects forced the clinical
BMS-275291 1,200 mg qd or placebo
trial to terminate early.
Paclitaxel
with
Well tolerated. The overall response rate of BMS-275291
BMS-275291 1,200 mg qd or placebo
arm was lower than that of the placebo arm (21.9% versus
+
carboplatin
2005
NSCLC in stage IIIB or IV
Phase III
without chemotherapy
Paclitaxel
S-3304
Sulfonamide
2005
Health male volunteer
Phase I
AZD1236
Non-hydroxamate
Neovastat
Mixed
(AE-941)
from
extract
Advanced solid tumors
n r u
Moderate to severe COPD
2012
Moderate to severe COPD
2003
shark
o J
Lung cancer
Phase II
Phase II
Phase I/II
with
Higher hypersensitivity and febrile neutropenia rates, but
BMS-275291 1,200 mg qd or placebo
no difference in MSS. No improved survival in advanced
al
Phase I
2011
carboplatin
p e
r P
10-800 mg bid versus placebo
derivatives 2007
+
f o
ro
36.4%).
800-3200 mg bid
Rizvi et al., 2004
Miller et al., 2004
Douillard et al., 2004
Leighl et al., 2005
NSCLC. Good tolerability. Good systemic exposure and free of MSS
Van Marle et al., 2005
at 800 mg bid. Good tolerability at 3200 mg bid. MMP was inhibited at
Chiappori et al., 2007
lower dose.
75 mg bid or placebo
Good tolerability. No significant treatment effects.
75 mg bid or placebo
The rates of adverse events were similar. No clinical
Magnussen
et
2011 Dahl et al., 2012
efficacy was observed. 30 to 240 mL/day bid
Good tolerability. No tumor responses were observed, but a
Latreille et al., 2003
dose-dependent increase in median survival time was
cartilage
found. 2002
Renal cell carcinoma
Phase II
60 mL/day bid or 240 mL/day bid
Good tolerability. 240 mL/day bid increased the median
Batist et al., 2002
survival time. 2010
NSCLC in stage III
Phase III
al.,
Chemotherapy with 120 mL/day bid
Good tolerability. No difference in overall survival, TDP
or placebo
and tumor response.
Lu et al., 2010
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Clinical trials resumed after nearly ten years of trials and tribulations
FP-025
Non-hydroxamate
2017
Healthy male subjects
Phase I
50 to 800 mg qd
NCT02238834. No results available, accessed Sept 4,
f o
2019.
GS-5745
mAb inhibitor
2019
Allergic asthma
Phase II
400 mg bid or placebo
2015
Advanced solid tumors
Phase I
(Andecaliximab)
2016
2018
2018
Active ulcerative colitis
Rheumatoid arthritis
Active Crohn’s disease
NA
1,800 mg IV, followed by 800 mg IV
Manageable safety profile for GS-5745 alone or in
Bendell et al., 2015
with chemotherapy
combination with chemotherapy. More subjects need to be
o r p
e
enrolled.
Either IV infusions (0.3 to 5.0 mg/kg
Good tolerability and no MSS
or placebo) every two weeks; or five
endoscopic and histological responses were positive. The
weekly SC injections (150 mg or
dose 1 mg/kg IV, 2.5 mg/kg IV and 150 mg SC were
placebo)
recommended.
r P
al
Clinical,
n r u
3 times.
hypersensitivity (13.3%).
800 mg GS-5745 + mFOLFOX6 IV
The treatment showed encouraging clinical activity without
every two weeks
additional toxicity, especially in first-line patients with an
Phase II
150 mg SC weekly, 300 mg SC
Good tolerability. No treatment effects were observed after
weekly, 150 mg SC every two weeks,
8 weeks.
Phase I
The highest
reported.
Good tolerability.
o J
Phase I
NCT03858686. Under recruiting, accessed Sept 4, 2019.
400 mg IV every two weeks for total
Gastric/gastroesophageal junction adenocarcinoma
2018
Phase I
NA
adverse event
was
Sandborn et al., 2016
Gossage et al., 2018
Shah et al., 2018
overall response rate at 50%. Schreiber et al., 2018
and placebo 2018
2016
Ulcerative colitis
Gastric/gastroesophageal
Phase
150 mg SC weekly, 150 mg SC every
Good tolerability. Terminated at 8 weeks because of lack of
II/III
two weeks
efficacy.
Phase III
800 mg GS-5745 + mFOLFOX6 IV
NCT02545504. No results available, accessed Sept 4,
every two weeks or placebo
2019.
Various
NCT03631836. Has no recruit yet, accessed Sept 4, 2019.
junction adenocarcinoma 2019
Recurrent glioblastoma
Phase I
doses
of GS-5745 with
Sandborn et al., 2018
Bendell et al., 2016
NA
Journal Pre-proof Bevacizumab 2019
Gastric/gastroesophageal
Phase II
junction adenocarcinoma
Nivolumab + GS-5745 800 mg IV
NCT02864381. Has no recruit yet, accessed Sept 4, 2019.
NA
every two weeks or Nivolumab alone
*Abbreviations: qd once daily; bid twice daily; tid three times daily; TDP time to disease progression; SCLC small-cell lung cancer; NSCL C non-small-cell lung cancer; MSS musculoskeletal syndrome; COPD chronic obstructive pulmonary disease; mAb monoclonal antibody; IV intravenous injection; SC subcutaneous administration
f o
l a n
J
r u o
r P
e
o r p
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The hemopexin domain has a four-blade propeller structure, which is linked to the catalytic domain via a flexible hinge (Fig. 1) (Cha et al., 2002). Research have demonstrated that the hemopexin domain and the catalytic domain are conformationally independent from each other. However, during substrate recognition and collagen hydrolysis, the hemopexin domain can move relative to the catalytic domain and allosterically manipulate enzymatic
f
activity (Bertini et al., 2008; Jozic et al., 2005; Overall and Butler, 2007). The term “allostery”
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here refers to the effect exerted by the distal structures, which regulate enzyme activity by
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conformational deformation (Sela-Passwell et al., 2010). The predominant advantage of
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allosteric drugs is that they provide non-competitive inhibition compared with traditional
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orthosteric compounds through the flexible dynamics of protein structure (Lu et al., 2014; Mitternacht and Berezovsky, 2011). This feature enables an allosteric inhibitor to be free
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from competition with the well-conserved catalytic site, with the advantage of avoiding
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off-target inhibition and preventing the occurrence of clinical side effects (Guarnera and
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Berezovsky, 2016). For MMPs, the long hinge is the prerequisite for flexible movement of the hemopexin domain. This long hinge regulates various functions of MMPs, including zymogen activation, oligomerization, substrate hydrolysis and inhibition through allosteric control (Sela-Passwell et al., 2010). Accordingly, targeting the hemopexin domain has been perceived as an effective means for designing selective inhibitors. For example, Remacle et al. (2012) reported a small molecule NSC405020 from the library of the DTP National Cancer Institute, which binds selectively to the hemopexin domain of MMP-14. This small molecule inhibits homodimerization of MMP-14 and the interaction between the hemopexin domain with the catalytic domain, thereby preventing degradation of type I collagen and halting
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tumor growth. Apart from allosteric control, exosites provide another alternative for selective MMPIs design. The term “exosite” is a relative concept for the catalytic site, which refers to the alternative binding site in MMP structures (Lauer-Fields et al., 2008). The major difference between allosteric sites and exosites is that the former communicates with the catalytic site
f
through a dynamic conformational change, whereas the latter encompasses a much broader
oo
concept. To date, several exosites have been identified, including the hemopexin domain,
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collagen binding domain and pro-peptide domain (Overall, 2002); their corresponding
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selective inhibitors had been designed. For example, Dufour et al. (2010) developed a
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structure-based inhibitory peptide targeting the MMP-9 hemopexin domain, which efficiently blocks MMP-9 dimer formation and cell migration. Xu et al. (2007) synthesized a peptide
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targeting the collagen binding domain of MMP-2, which inhibits hydrolysis of type I and
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type IV collagen. Scannevin et al. (2017) identified a highly-selective compound named
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JNJ0966, which binds to the pro-peptide domain of MMP-9 and inhibits activation of pro-MMP-9 without affecting MMP-1, -2 and -14. Because the binding affinity of most exosites for substrates is typically low (10 -6 - 10-7 M), the IC50 of exosite inhibitors is in the micromolar range. Hence, exosite inhibitors do not manifest outstanding superiority over the allosteric inhibitors (Overall and Kleifeld, 2006a; Scannevin et al., 2017; Xu et al., 2007). It has been suggested recently that each MMP possesses its unique exosites or “hotspots” that may be targeted individually due to difference in their amino acid composition and diversity in geometry (Levin et al., 2017). In the future, highly-selective MMPIs may be synthesized via the combined inhibition of both the active
Journal Pre-proof site and the MMP-specific “hotspots”.
3. On-going research techniques Progress in medicine is always accompanied by technological innovation and knowledge extension. The aforementioned four generations of MMPIs are vivid examples of progressive cognitive advancement, with the inhibition target expanding from the limited small zinc
oo
f
binding site to full- length MMP structures. From a technological perspective, however, there has been little advancement on MMPI development, as they were mainly small molecules or
pr
peptides selected from biochemical or biophysical libraries that lacked direct synthesis based
which have greatly improved MMPI design,
namely
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two on- going techniques,
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on specific “hotspots” (Rouanet-Mehouas et al., 2016). In the following part of the review,
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antibody-based inhibitors and protein-engineering inhibitors, will be presented (Fig. 4).
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3.1 Antibody-based inhibitors
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Antibody, also known as immunoglobulin, is a large Y-shaped protein which binds to an antigen via the Fab variable region (Litman et al., 1993). Monoclonal antibodies (mAb) are antibodies that are produced by identical immune cells that are all clones of a unique parent cell. For almost any substance, it is possible to produce the corresponding mAb via phage display, single B cell culture, single-cell amplification and single plasma cell interrogation technologies. These techniques provide useful and importa nt tools in biochemistry, pharmacy and molecular biology investigations. To date, several mAbs directed against MMPs have been developed, with outstanding selectivity. One of the first MMP-9 antibodies reported was REGA-3G12, a highly-selective
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f
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antibody against MMP-9, but not MMP-2 (Paemen et al., 1995). REGA-3G12 specifically targets the N-terminal region (Trp116 - Lys214 ) of the catalytic domain of MMP-9, but not the catalytic zinc ion or the collagen binding domain (Martens et al., 2007). DX-2400 is an antibody
isolated
from a phage display
library.
It targets MMP-14
and
the
MMP-14-dependent proMMP-2 processing, decreasing MMP activity up to 70% in animal models (Devy et al., 2009). Unlike DX-2400, the antibody LEM-2/15 only selectively inhibits MMP-14 catalytic activity toward gelatin and collagen type I without affecting
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proMMP-2 activation and MT1-MMP dimerization (Udi et al., 2015). Another antibody of MMP-14, named 9E8, has no effect on MMP-14 hydrolysis, but inhibits proMMP-2 activation (Shiryaev et al., 2013). Although DX-2400, LEM-2/15 and 9E8 are all selective MMP-14 antibody inhibitors, subtle differences exist in their regulation of downstream functions (Winer et al., 2018).
f
Fig. 4 The evolution of MMP inhibitors. Cognitive advancement (blue line) and technique innovation
oo
(orange line) are two pillars that support the progression of MMPIs. They not only move forward
pr
individually, but also synergistically create the first to fourth generation of MMPIs (represented by red dots)
e-
and the potential future generations by their convergence. The rationale of the four generations of MMPIs
Pr
are manifested by four representative pictures (A-D) respectively, and their features are listed on the right. In the close-up views, the catalytic zinc ion is portrayed as a green sphere; the active site His are portrayed
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as sticks in blue and white; and the zinc ion interactions are represented by purple dash lines. (A) MMP-13
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complexed to a hydroxamate-based inhibitor (PDB code: 2D1N, two chelating linkages are formed
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between Zinc ion and inhibitor). (B) A carboxylic acid inhibitor in complex with MMP-3 (PDB code: 1HY7, one chelating linkage is formed between Zinc ion and inhibitor). (C) Crystal str ucture of the complex between MMP-8 and an inhibitor enters into S 1 ’ pocket (PDB code: 3DPE, no chelating linkage is formed between Zinc ion and inhibitor). (D) Structure of a selective antibody inhibitor (GS-5745) bound to MMP-9 (PDB code: 5TH9, targeting at exosites other than catalytic domain). PDB: Protein Data Bank.
Another MMP-9 monoclonal antibody, GS-5745, is a highly-selective antibody (IC 50 = 0.148 nM) targeting four residues (R162, E111, D113, and I198) near the catalytic zinc ion. GS-5745 exerts allosteric control over tumor growth and metastasis in a colorectal carcinoma
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model (Marshall et al., 2015). To the best of our knowledge, GS-5745 (Andecaliximab) is the only mAb inhibitor that has undergone clinical trials (Table 1). A Phase I trial results suggest that GS-5745 is well tolerated by patients with ulcerative colitis and produces positive clinical, endoscopic and histological outcomes (Sandborn et al., 2016). Another Phase I trial examined the effect of GS-5745 in combination with modified-FOLFOX6 (5- fluorouracil,
f
leucovorin and oxaliplatin) in human subjects with advanced gastric /gastroesophageal
oo
junction adenocarcinoma. The GS-5745 treatment achieved target engagement with no
pr
dose-limiting toxicity, with tuning down of collagen neoepitope levels (MMP-9) that
e-
suggested a therapy-related effect (Shah et al., 2018). The positive results of this Phase I trial
Pr
led to the implementation of a Phase III trial which is currently being conducted with the same treatment on the same disease with a larger anticipated population (NCT02545504,
al
accessed Sept 4, 2019) (Bendell et al., 2016). Except for these ongoing clinical trials, more
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GS-5745 trials are now recruiting volunteers to explore its potential effects in different
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diseases (NCT03631836 and NCT02864381, accessed Sept 4, 2019). Despite the promising effect of antibody-based MMPIs, there are still problems that need to be addressed. For example, binding sites of antibodies are in a planar or concave shape, which do not fit well with the active sites of MMPs (pocket shape) (Levin et al., 2017). To solve this problem, Sircar et al. (2011) suggested replacing the human antibody H3 with the camelid antibody CDR-H3, which is a much longer convex-shaped paratope. After synthesizing a library of CDR-H3 modified antibodies, Nam et al. (2016) evaluated the inhibitory potency of targeting the catalytic domain of MMP-14. The results turned out to be overwhelmingly positive (IC 50 = 9.7 nM), and the hybrid antibody showed higher selectivity
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toward MMP-14 compared with MMP-2 or MMP-9. Despite these positive results, more research is needed to evaluate the biosafety and reproducibility in vivo. Apart from the shape fitness problem, the use of antibodies is limited to intravenous or subcutaneous administration, rather than oral administration, which strictly restricts its application (Vandenbroucke and Libert, 2014). Further studies are required to ameliorate antibody usage
f
in a more friendly and convenient way.
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3.2 Protein-engineered inhibitors
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Protein-engineering technologies, including computational design and directed evolution,
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have been reported to be effective and valuable methods in generating desired proteins with
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novel biologic functions (Chao et al., 2006; Levin et al., 2013). Computational design facilitates the exploration of an astronomical number of protein sequences in silico to screen
al
optimal protein binders, which are then experimentally verified by site-directed mutagenesis
rn
(Mohan et al., 2016). Directed evolution, which is based on gene mutant libraries, screens the
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desired proteins using high-throughput technology and display systems (phage, bacterial, yeast, etc.) by directed force (Banta et al., 2013). With the combination of these two methods, the protein-engineering technique appears to be the optimal technology for screening highly-selective MMPIs in an economic and efficient manner (Gebauer and Skerra, 2009). The most popular group of MMPIs derived from protein-engineering is a family of engineering N-terminal TIMPs. As previously discussed, there are four endogenous TIMPs (TIMP1-4) in the human body that form a 1:1 complex with MMP in the catalytic domain using their N-terminus peptide non-selectively (Maskos and Bode, 2003). The isolated N-TIMP is a stable peptide that retains inhibitory ability against various MMPs (Murphy et
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al., 1991). Because of their relatively small sizes, N-TIMPs may be generated via microbial cultures to create potent inhibitors for direct delivery into cancer cells (Mohan et al., 2016). Accordingly, N-TIMPs have been perceived as convenient backbones for protein-engineering to increase MMP selectivity. Harnessing on the favorable reports that binding affinity increases up to 10- fold with
f
only one site mutation of the N-TIMP (Grossman et al., 2010; Nagase and Brew, 2002;
oo
Sharabi et al., 2014), Wei et al. (2003) increased the mutant sites to three
pr
(Thr2Ser/Val4Ala/Ser68Tyr) and reported that N-TIMP-1 binds to MMP-3 with picomolar
e-
affinity. With the help of computational design, Arkadash et al. (2017) screened 7 potential
Pr
positions in N-TIMP-2 that may augment binding affinity. With 20 amino acids present in seven positions, a mutant library comprising over 1.3 × 109 combinations is generated. Using evolution
and
yeast
surface
display,
N-TIMP-2
with
five
mutations
al
directed
rn
(Ile35Met/Asn38Asp/Ser68Asn/Val71Gly/His97Arg) has been shown to be the mo st potent
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inhibitor against MMP-14 (Ki = 0.9 pM).
4. Future prospects of next generation of MMPIs The past decade was a relatively repressive time for the development of MMPIs. Almost no clinical trial was conducted, and increasing doubts have been raised on the feasibility of MMPIs in treating the associated diseases. With the development of X-ray crystallography, nuclear magnetic resonance spectroscopy, high-throughput screening and computational methods, the full- length structures of MMPs are gradually recognized. The S’ pocket, allosteric sites, and exosites brought new innovation to MMPI design. The interaction
Journal Pre-proof between monoclonal antibody with unique “hotspots” and the protein engineering technique provide efficient tools for direct protein synthesis and screening. Phase I clinical trial for GS-5745 had been successfully implemented and Phase III trial is currently being conducted after an intellectual vacuum for almost 10 years (Bendell et al., 2016). All these events have created a new era for MMP inhibitors (Fig. 5). In the following section, we provide possible
f
future directions based on our own perceptions.
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4.1 Enhancing binding site specificity
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The combination of different inhibition sites and different technologies has been perceived as the most feasible way to increase the selectivity of MMPIs. Udi et al. (2013) proposed the notion of the existence of a unique region in individual MMPs that manifests the highest binding energy for ligand binding. These regions are potential selective “hotspots”
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rn
al
Pr
e-
pr
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f
for drug design. Because of technological limitations, the authors had to synthesize a series of
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polymers with different degrees of branching to screen the most selective entity through time-consuming experiments. With the advent of protein engineering techniques, one can now build a mutant library based on the unique amino acids held by different MMPs in silico, and screen the highly potent selective inhibitors by computational simulation (Arkadash et al.,
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rn
al
Pr
e-
pr
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f
2017). The early MMPIs were small molecules or peptides that could only target one binding
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site, or extended to the nearby side pockets at most. With understanding of the hotspots of each MMP, macromolecular proteins, which inhibit the catalytic site as well as specific hotspots simultaneously, may be the future goal for protein engineering techniques. 4.2 Smart drug delivery systems for achieving selectivity
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Apart from MMP binding site specificity, smart drug delivery systems, which directly
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target the designated position of MMP inhibition, are another important method to reduce off-target side effects. Matrix metalloproteinases play important roles in tumor-associated processes such as metastasis, tumor growth, angiogenesis, apoptosis and immune modulation (Fingleton, 2006). Upregulation of MMPs have been found to be positively-correlated with the development of cancer (Egeblad and Werb, 2002). For example, in benign ovarian tissues, the MMP-2 concentration is around 0.47 μg/mg, whereas the value increases to 0.78-1.2
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μg/mg in ovarian cancer patients, depending on the cancer stage (Schmalfeldt et al., 2001;
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Zucker et al., 1992). Hence, representative MMPs in specific diseases may be utilized as
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therapeutic targets for MMP-responsive “smart” drug delivery systems (Yao et al., 2018).
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Currently, three MMP-responsive drug release methods have been proposed, namely, linker cleavage, structure disassembly and membrane “uncorking” (Yao et al., 2018). In these three
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methods, the drug molecules are either conjugated to the polymer via an MMP-sensitive
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linker, or encapsulated in a degradable nanoparticle or opened by a specific MMP. By using
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the linker cleavage and membrane “uncorking” methods, Purcell et al. (2014) synthesized an injectable and bioresponsive MMP-sensitive hydrogel containing a recombinant tissue inhibitor of MMPs (rTIMP-3) (Purcell et al., 2014). This hydrogel/rTIMP-3 system produces minimal release in non-targeted tissues (that is, lack of MMP activity) and significantly suspends tissue remodeling in myocardial infarction. Further steps may be implemented, such as encapsulating highly-selective mAb inhibitors within MMP-responsive nanoparticles. Such a strategy may change the drug delivery method from parenteral injection to more patient-friendly oral administration without adversely affecting the function of mAb inhibitors.
Journal Pre-proof Fig 5. Timeline listing milestones in the discovery, design and development of MMPIs
4.3 Thorough understanding of MMPs in health and disease A thorough understanding of the functions of different MMPs in different diseases under different spatiotemporal conditions should be the ultimate goal for scientists in this research
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arena. Numerous reports have indicated that MMPs play different roles in different biological systems, such as substrate recognition, signal transmission and protein-protein interactions.
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These substrates and signal molecules together with MMPs form a dynamic web – the
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“protease web”, which entangle with each other and maintain homeostasis in a subtle balance
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(Overall and Kleifeld, 2006b). Subsequently, a single MMP can degrade/activate different
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substrates that may exert opposite effects on physiologic function or disease progression. As
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mentioned previously, the three different mAb inhibitors (DX-2400, LEM-2/15 and 9E8) all
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target at MMP-14 selectively, but their downstream substrates vary from each other (Devy et al., 2009; Shiryaev et al., 2013; Udi et al., 2015). The latest MMP research opens new views in the understanding of previously unrecognized cell physiology. Working with the neamtode C. elegans, Kelley et al. (2019) demonstrated that in the absence of MMPs, invasive cancerous cells can still penetrate the basement membrane via an alternative method. This is achieved via the formation of F-actin-rich protrusions that physically breach and displace the basement membrane (albeit much slower than MMP- mediated degradation). If such a biological process really occurs in human cells, the theory on prevention of cancer metastasis via MMP inhibition will no longer
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be valid (Castro-Castro et al., 2016; Kessenbrock et al., 2015). Although the role of MMPs in cancer metastasis may be mellowed, their regulation on other aspects of cancer progression, as well as the whole “protease web” should not be overlooked. A subtle shift of emphasis from direct blocking of MMPs to targeting the MMP substrate and “after metastasis” processes may be the future direction for developing new generations of MMPIs. This latest
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research emphasizes that sophisticated and complex cellular pathways mediated by different
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MMPs in different diseases need to be further understood. In addition, specific signal
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peptides and structure binding sites need to be further characterized, and well-designed
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clinical trials need to be further implemented in order for MMP-strategized therapeutics to be
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successful.
5. Concluding remarks
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It has been nearly five decades since the discovery of MMP in tadpoles. Since then, the
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progress in deciphering the roles of MMPs in human physiologic functioning and disease
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progression has been nothing short of phenomenal. Although a plethora of reviews on MMP inhibitors have recently been published and provided insights on future development of MMP inhibitors (Fields, 2019a; Fischer and Riedl, 2019; Fields, 2019b; Young et al., 2019; Fischer et al., 2019; Cerofolini et al., 2019), this review is original in the following aspects: (1) the historical development of MMPIs was described under two perspectives, cognitive advancement and technique innovations so that the characteristics of different MMPIs and the reasoning behind the supersession could be easily understood; (2) In the previous reviews, the MMPIs were only defined up to the third generation, the catalytic domain inhibitors. In the current review, the fourth generation MMPIs, the allosteric control and exosit es control
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inhibitors, were described and added to cover the full spectrum of MMPIs; (3) Apart from the synthesized MMPIs, the natural MMPIs derived from plants and marine environments were also included; their pros and cons were discussed; (4) After almos t 10 years of intellectual vacuum, the Phase I clinical trial of newly antibody-based inhibitors had been successfully implemented and Phase III trial is currently being conducted. These novel clinical trials have
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brought new hope for future developments of MMPIs and they have been summarized along
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with previous clinical trials in the current review. Although research on MMP inhibitors was
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not as successful as anticipated, the fruits derived from previous studies are invaluable for
should
be
cautiously
optimistic
that
structurally-selective
and
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profession
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shaping future research. With the development of new experimental techniques, the
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spatiotemporally-specific MMPIs with minor off-targeting effects will blossom.
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Conflict of Interest Statement
References
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The authors declare that there are no conflicts of interest.
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