Chapter 14 Recent Progress in the Development of Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase

CHAPT ER

14 Recent Progress in the Development of Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase Mark D. Wittman, Upender Velaparthi and Dolatrai M. Vyas

Contents

1. Introduction 2. IGF-1R Signaling 3. ATP-Competitive Inhibitors 3.1 5,7-Disubstititued pyrrolopyrimidines 3.2 5-7-Disubstituted pyrrolopyrimidine isosteres 3.3 2,4-Disubstituted pyrimidines 3.4 2,4-Disubstituted pyrimidine isosteres 3.5 Miscellaneous heterocyclic systems 4. Non ATP-Competitive Inhibitors 4.1 Catechols 4.2 Natural lignans 5. Conclusions References

281 282 283 283 284 286 288 290 293 293 295 295 296

1. INTRODUCTION Cancer therapeutics that target growth factor receptors are gaining prominence in the successful treatment of a wide variety of malignancies. Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492-7660, USA Annual Reports in Medicinal Chemistry, Volume 44 ISSN: 0065-7743, DOI 10.1016/S0065-7743(09)04414-5

r 2009 Elsevier Inc. All rights reserved.

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Kinase activation or overexpression is often pivotal in triggering the aberrant signaling pathways typical of the malignant cellular phenotype. The identification of appropriate kinase targets for inhibition with small molecules remains an active area of research for oncology drug discovery. Since the early observations of the mitogenic properties of insulin [1], interest in the insulin-like growth factor-1 receptor (IGF-1R) signaling pathway has been increasing. The convergence of efficacy data for an IGF-1R-specific antibody [2] and epidemiological findings [3] have prominently positioned IGF-1R among the emerging cell signaling pathways currently being explored for cancer therapy. Several approaches to suppress IGF-1R signaling are actively being investigated. These include the use of monoclonal antibodies (mAb) directed against the extracellular ligand-binding domain of the receptor, modulation of the circulating levels of ligand (IGF-1 and IGF-2) through the IGF-binding proteins (IGFBPs), and small molecule kinase inhibitors of IGF-1R. The mAb approach has yielded the first IGF-1R inhibitors to enter clinical development [4–6]. The advantage of the mAbs is their inherent selectivity for IGF-1R over the closely related insulin receptor (IR). However, the lack of cross-reactivity with IR may adversely affect antitumor efficacy since the IR-A isoform exhibits high affinity for IGF-2 and is expressed at high levels in some breast cancers [7]. In addition, the downregulation of IGF-1R by siRNA in breast tumor cell lines sensitizes cells to insulin activation of downstream signaling pathways [8]. The most advanced mAb, CP-751871, is currently in phase III trials. Responses have been reported in advanced adrenocortical cancer and various sarcomas [9]. CP-751871 has also shown responses in non-small cell lung cancer (NSCLC) in combination with paclitaxel and carboplatin [10]. These studies provide proof of concept for the importance of inhibiting IGF-1R signaling in cancer therapy. Several earlier reviews of IGF-1R inhibitors have appeared [11–15]. This chapter will focus on the most recent advances in small molecule inhibitor design and specifically highlight those inhibitors that are entering the early stages of clinical development. Small molecule inhibitors of IGF-1R fall into two sub-categories: those that target the ATP-binding pocket of IGF-1R kinase (ATP-competitive) and those that target the substrate-binding site (non ATP-competitive). The most advanced small molecules are ATP-competitive kinase inhibitors. The greatest challenge for ATP-competitive inhibitors is achieving selectivity versus other kinases, including the closely related IR which shares high overall sequence homology (84%) and complete homology among the residues that contact ATP in the kinase-binding domain [16].

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2. IGF-1R SIGNALING IGF-1R is a heterotetramer composed of two extracellular a-subunits that contain the ligand-binding domain and two b-subunits that contain the cytoplasmic kinase domain. Binding of the ligands IGF-1 and IGF-2 to the extracellular domain of the receptor leads to autophosphorylation of the cytoplasmic b-subunit and activation of the intrinsic kinase activity of the receptor. Activation results in the phosphorylation of insulin receptor substrates (IRS-1-4) and Src-homology containing adapter protein (Shc). These in turn activate the PI-3K/Akt/mTOR survival pathway and the mitogenic RAS/Raf/MAPK pathway respectively [17,18]. IGF1R signaling has pleiotropic effects ranging from cell proliferation, differentiation, and migration to regulation of the apoptotic machinery. The crosstalk observed between epidermal growth factor receptor (EGFR) and IGF-1R signaling suggests wide potential for using IGF-1R inhibitors in combination therapy with other targeted agents, cytotoxics, and radiation therapy. IGF-1R activation has also been implicated in the development of resistance toward trastuzumab treatment in breast cancer [19] and lung cancer [20]. mAbs

Insulin

IGF-I

IGF-I IGF-II

pp p Insulin R

p p

pp p

IGF-1R/IR

IGF-1R

IRS PI3K Akt mTOR Survival

Shc Grb2/SOS Ras MAPK Proliferation

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3. ATP-COMPETITIVE INHIBITORS 3.1 5,7-Disubstititued pyrrolopyrimidines The 5,7-disubstituted pyrrolopyrimidines were among the first chemotypes described as inhibitors of IGF-1R. NVP-AEW-541, 1 [21], and NVPADW742, 2 [22], are the most studied members of this class. To date, no structure-activity relationship (SAR) studies have been published for this series, but additional analogs are exemplified in a patent application [23]. Pyrrolopyrimidine 1 is a 150 nM(IC50) inhibitor of IGF-1R kinase and is equipotent versus IR. Despite the lack of selectivity in the in vitro kinase assay, 1 is 27-fold selective over IR in a cellular context. The authors suggest that the cellular selectivity arises from conformational differences that exist between the native forms of the enzymes in the cellular context, which are not present in the recombinant enzymes [21]. It remains to be seen if the observed cellular selectivity will translate into a clinical benefit compared to other non-selective inhibitors of IGF-1R/IR signaling. This compound has been extensively studied in vitro and in preclinical animal models [24–26] and was reported to have entered phase I clinical trials in 2004, but nothing has been published to date on the clinical findings.

O NH2

R=

N 1

N N

N

R=

N 2

R

3.2 5-7-Disubstituted pyrrolopyrimidine isosteres 3.2.1 Imidazopyrazines Several isosteric replacements of the pyrrolopyrimidine core have been investigated by various groups. In general, these isosteric scaffolds possess the same cellular selectivity described for the pyrrolopyrimidines

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(Section 3.1). Included among these scaffolds are the imidazopyrazines [27–29]. Initial lead optimization efforts focused on replacing the benzyl ether present in 1 and 2 to improve metabolic stability and potency. These studies identified an advanced lead, PQIP, 3 (IC50 ¼ 24 nM) [30]. In a Geo colon carcinoma model, 3 is able to inhibit 80% of IGF-1R phosphorylation within the tumor resulting in 70–80% inhibition of tumor growth (%TGI) after a daily oral dose of 25 mg/kg [31]. Further absorption, distribution, metabolism, and excretion (ADME) optimization led to the clinical candidate OSI-906, 4 (IC50 ¼ 35 nM) with a high degree of selectivity over other kinase targets. Imidazopyrazine 4 shows a wide range of anti-proliferative effects in colorectal, NSCLC, breast, pancreatic, and rhabdomyosarcoma with TGI ranging from 53% to W100% in preclinical models at oral doses of 30–60 mg/kg [32].

N

N NH2

NH2 N

N

N

N

N

N

3

4 OH

N

N

3.2.2 Pyrazolopyrimidines From a series of pyrazolopyrimidine inhibitors, A-928605, 5, was identified with both IGF-1R (IC50 ¼ 35 nM) and EGFR activity (IC50 ¼ 65 nM) [33]. The dual IGF-1R/EGF activity was further optimized to take advantage of the crosstalk between IGF-1R and EGFR, leading to compound 6, which represents the optimal balance of IGF-1R (IC50 ¼ 81 nM), EGF (IC50 ¼ 58 nM), and ErB-2 (IC50 ¼ 54 nM) activity, cellular activity, and pharmacokinetics [34].

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3.2.3 Pyrrolotriazines The pyrrolotriazine scaffold, 7, has also been used to optimize for IGF-1R potency. A patent application specifically claiming these compounds as IGF-1R inhibitors has appeared, although no IGF-1R inhibitory data is disclosed [35].

R1 HN

HN

HN N

NH2

NH2

NH2

N

N

N N N

N

N MeO

Cl

N

N

N

N

N

N R2

5

6 N

7 HN

O

OMe

3.3 2,4-Disubstituted pyrimidines A number of inhibitors utilize the pyrimidine scaffold with various substitutions at the 2 and 4 positions. Pyrimidine 8 is representative of one such series with IGF-1R activity (IC50o50 nM) [36,37]. From this series, XL-228 (structure not disclosed) has advanced into the clinic. XL-228 is a multi-targeted protein kinase inhibitor with singledigit nanomolar activity reported for IGF-1R, IR, Src, AurA/B, Fak, FGFR1,2,3 (fibroblast growth factor receptor 1,2,3), and BCR-Abl. Ph+CML and Ph+ALL patients were administered a 1-h intravenous infusion of XL-228 at a dose of 10.8 mg/kg on a once-weekly schedule. The dose-limiting toxicities observed included hyperglycemia and syncope [38]. A patent has been filed specifically claiming compound 9, which has an IC50 of 4.3 nM versus IGF-1R with eightfold selectivity over the IR [39]. The aminopyrazole element is common to both 8 and 9 and most likely forms a hydrogen bond triad with the hinge region of the kinase.

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NH

N

N

NH N

HN

HN

N O

N HN

N

N

N O

N H

MeO

N

N

N

8

9

N

3-Aminoquinoline-containing pyrimidines are also claimed as IGF-1R inhibitors. Pyrimidine 10 is equipotent against IGF-1R and IR (IC50 ¼ 25 nM) and demonstrated 33% tumor growth inhibition at 100 mg/kg in a Calu6 tumor xenograft model. Despite the lack of in vitro selectivity over IR, no significant effects on blood glucose levels were observed following insulin and glucose challenge [40]. The closely related compound 11 is a 120 nM (IC50) inhibitor of IGF-1R [41]. N N

O

HN

H N

O R=

N N

N H

R

N H

10

11

The 2-aminoimidazole-substituted pyrimidine, 12, has modest IGF-1R activity (IC50 ¼ 150 nM) [42]. The related pyrimidine, TEA 226, 13, is described as a dual inhibitor of IGF-1R and FAK with inhibitory effects on mTOR signaling in esophageal cancer cells indicating a potential application in esophageal cancer [43]. O N

N H N H

HN

O H N

N N

HN

O

Cl

N N

N H

N 12

N H 13

O

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Imidazo[1,2-a]pyridine inhibitor 14 was identified as a screening hit with modest IGF-1R activity (IC50 ¼ 180 nM). C-2 optimization coupled with the reversal of the amide bond connectivity culminated in GSK1904529A, 15, which is equipotent against IGF-1R and IR in a receptor autophosphorylation assay. The compound has 35–124 nM (IC50) potency in cell lines representing multiple tumor types and is orally bioavailable in rat, dog, and monkey [44,45].

F

F O

N

N

H N

N N H F

F

N

H

N

O MeO

N H

H N

N

N

14

N OMe

15

N N

N

N O

S

O

3.4 2,4-Disubstituted pyrimidine isosteres The pyrrolotriazine BMS-754807, 16, has recently been presented as a 2 nM (IC50) inhibitor of IGF-1R with no selectivity over IR and is orally active in a transgenically derived, IGF-1R-driven, IGF-1R Sal tumor model at a dose of 3 mg/kg [46]. The compound is also orally active at 3 mg/kg in the IGF-1R-driven sarcoma model, Rh41, and the Geo colon carcinoma model at 12 mg/kg. The combination of 16 plus cetuximab (EGFR inhibitor) is therapeutically synergistic. Initial single ascending dose studies in normal healthy volunteers demonstrated good bioavailability and tolerability. Further clinical evaluation is ongoing [47]. A similarly substituted triazine, 17, is described in the patent literature which inhibits 96% of tumor growth in the IGF-Sal tumor model at a 3 mg/kg oral dose [48].

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N

NH

N

HN

NH

HN O

H N

N N

O N N

N

N

H N

N

N F

N

N

N N

O

16

17

OMe

Several pyrrolopyrimidine-based inhibitors of IGF-1R have also been described. The 4,6-bis-anilino-1H-pyrrolo[2,3,-d]pyrimidine, 18, has an IC50 of 5 nM in an enzymatic assay and an IC50 of 109 nM in a cellular assay of IGF-1R phosphorylation [49]. Further optimization at C-5u provided compounds with single-digit nanomolar inhibition of IGF-1R in enzymatic and cellular assays. Pyrrolopyrimidine 19 is a potent IGF-1R inhibitor (enzyme IC50 ¼ 2 nM, cellular IGF-1R phosphorylation IC50 ¼ 85 nM), W1,000-fold selective over the JNK1 and JNK3 kinases, and has 98% oral bioavailability in rats [50]. The N,N,-dimethyl glycinamide forms a hydrogen bond with the backbone NH of Asp1056. Indoline 20 was designed to prevent the acid-mediated cyclization of the pyrimidine moiety onto the pendant carboxamide observed with 18 and 19. This compound maintains enzymatic and cellular potency while improving chemical stability (t1/2 ¼ W1,000 h at 231C in 0.1N HCl) [51].

NH2

F

NH2

O

O R= R

HN

HN

N

N

19 HN MeO

N H

N

18

HN

N H

N

MeO R=

O

N N N

N

NMe2

20

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3.5 Miscellaneous heterocyclic systems 3.5.1 Benzimidazoles Benzimidazole-pyridones were among the early small molecule chemotypes described as ATP-competitive inhibitors of IGF-1R. The initial screening hit was optimized for potency and Cytochrome p-450 (CYP) inhibition to provide an early lead structure, BMS-536924, 21 [52–60]. This compound inhibits both IGF-1R and IR with equal potency (IC50 ¼ 120 nM), is selective versus other kinases, inhibits the phosphorylation of Akt and MAP kinase (MAPK) in cells, and blocks proliferation in a wide variety of human cancer cell lines including colon, breast, lung, pancreas, prostate, sarcoma, and multiple myeloma (IC50’s of 110–460 nM). Tumor growth inhibition is observed in vivo when dosed orally in the IGF-1R Sal tumor model [46] and in a broad range of human tumor xenografts such as Colo205, Geo, and RD1 (50–100 mg/kg). Oral bioavailability is observed across all species, and a twofold window between antitumor efficacy and glucose elevation at the efficacious dose was reported [55]. Benzimidazole 21 reverses IGF-1R-induced transformation of mammary epithelial cells, blocks proliferation, and restores apical-basal polarity in MCF-7 cells [56]. The potential for CYP inhibition, time-dependent CYP inhibition, and pregnane X receptor (PXR) transactivation was reduced by replacing the morpholine ring in 21 with a C-linked piperidine. Combining this modification with the chloropyrazole side chain [57] led to the discovery of BMS-695735, 22, which demonstrates in vivo efficacy in the IGF-Sal, Colo205, Geo colon carcinoma, and JJN3 multiple myeloma models when administered orally at doses between 50 mg/kg and 100 mg/kg [59]. O N

H N

F

O

N

O

H N

NH

N

NH

N HN

HN

HO N N Cl

21

Cl

22

3.5.2 Bicyclic pyrazoles The patent literature also describes bicyclic pyrazole inhibitors of IGF-1R. These structures represent a significant departure from other reported

291

Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase

leads. Limited IGF-1R activity is presented in these patents with 23 being the most potent example reported (IC50 ¼ 49 nM) [61–63].

N N H N

N HN

O

HN

N H O

N

O S O

23

F

F

3.5.3 Ureas One of the most promising diarylurea (DAU) inhibitors is PQ401, 24, which inhibits the autophosphorylation of IGF-1R in human cultured MCF-7 cells with an IC50 of 12 mM. Treatment of MCNeuA cells implanted into mice with 24 reduced tumor growth when dosed three times per week intraperitoneally [64]. Lead optimization around a series of 3,5-disubstituted 1H-pyrrolo[2,3-b]pyridines led to the identification of compound 25, which shows potent in vitro kinase activity (IC50 ¼ 21 nM) and inhibits IGF-1R phosphorylation in cells (IC50 ¼ 68 nM) [65].

O H N

H N

N

O

O

H N

H N

N O

O

24

Cl

25 N

N H

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3.5.4 Pyrrolocarboxaldehydes Pyrrolocarboxaldehydes have been disclosed as monocyclic ATPcompetitive inhibitors of IGF-1R [66]. Aldehyde 26 is modestly selective versus IR in enzymatic and cell-based assays (IGF-1R, IC50 ¼ 490 nM; IR, IC50 ¼ 2 mM) and forms a reversible, covalent adduct with the kinase active site. CHO HN

O

OEt O O

26

3.5.5 Quinolines IGF-1R inhibitors have also been built around the quinoline core structure. Optimization of the cyanoquinoline template provided 27 with potent IR (IC50 ¼ 2 nM) and IGF-1R (IC50 ¼ 9 nM) activity as well as activity in a cellular myloid assay with an IC50 of 90 nM [67]. Cl S

N

H N

R2

N HN MeO

R1

O

CN NH

O

N

O R1

Br

28

N

R2

N

N

29 27

O

N

N

N H

The isoquinolinedione 28 was identified as an initial micromolar hit that binds at the ATP-binding site in a similar mode to the

293

Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase

benzimidazoles described above (Section 3.5.1). Optimization of R1 and R2 culminated in compound 29 (IGF-1R, IC50 ¼ 319 nM), which is equipotent against IR and has improved selectivity over cyclindependent kinase (CDK)-4 [68].

4. NON ATP-COMPETITIVE INHIBITORS The discovery and development of IGF-1R selective, non ATP-competitive inhibitors has been slow relative to ATP-competitive inhibitors due to the inherent medicinal chemistry challenges involved in optimizing potency for the more open substrate-binding site, requiring the use of peptide or peptidomimetic elements. To date, the two main classes of non ATP-competitive inhibitors are catechols and naturally occurring lignans.

4.1 Catechols A systematic discovery effort to design more potent and selective IGF-1R substrate inhibitors commenced with the screening of the ‘‘tyrphostins’’ (Tyrosine Phosphorylation Inhibitors) that are synthetic catechols previously shown to inhibit EGFR [69–71]. These efforts identified biscatechols 30 [72,73] and 31 [74]. Tyrphostin 30 has activity against IGF-1R (IC50 ¼ 61 nM), IR (IC50 ¼ 113 nM), and EGFR (IC50 ¼ 370 nM) receptor kinases. Based on the published X-ray structure of the kinase domain of IR, the catechol rings in 30 function as phosphate bioisosteres of phosphotyrosines 1158 and 1162 [71]. The novel tertiary amine catechol 31 inhibited the IGF-1R receptor with an IC50 of 170 nM in a cell-free kinase assay (inhibition of polyTyrGlu (pGT) phosphorylation catalyzed by IGF-1 receptor) and exhibited inhibitory IC50 values in the range 4–6 mM in a colony formation assay in soft agar for three cell lines (MCF-7, LNCap, PC-3). HO

O

N

OH

HO

HO

OH OH

CN OH

HO

O O

30

31

SAR and lead optimization efforts to mitigate metabolic liabilities due to the catechol rings led to some moderately potent benzoxazolone

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analogs 32a–c [73]. No selectivity over IR was observed. Replacement of both catechols with benzoxazolone rings led to inactive compounds.

R1

32a

R2

32b

CN 32

IGF-1R IC50

O

OH

N H

OH

~370 nM

O

O R1

R2

H N

OH

O

OH

~430 nM

O H N

HO 32c

~600 nM O

O

HO

To date, none of the synthetic catechols or their close analogs discussed above have progressed into clinical development. The naturally occurring bis-catechol, nordihydroguaiaretic acid, 33 (NDGA, INSM-18), has advanced to phase II clinical trials using continuous oral dosing for the treatment of prostate cancer [75–77]. NDGA inhibits IGF1R phosphorylation of a synthetic nonspecific tyrosine kinase substrate and proliferation of MCF-7 breast cell line with an IC50 of 0.9 and 24.6 mM respectively. Some early positive clinical data is now emerging from the prostate trial with respect to reduction in prostate-specific antigen (PSA) levels and delay in PSA doubling time in patients. Doses up to 2,500 mg/ day are tolerated with minimal toxic effects. NDGA has Her-2 receptor kinase and 15-lipoxygenase inhibitory activity. Although there is no direct mention of 33 being a non ATP-competitive IGF-1R inhibitor, it is a non ATP-competitive inhibitor of FGFR3 tyrosine kinase [78].

OH HO OH HO 33

Small Molecule Inhibitors of Insulin-Like Growth Factor-1 Receptor Kinase

295

4.2 Natural lignans The naturally occurring lignan picropodophyllotoxin (PPP) or AXL-1717, 34, has recently advanced into human clinical trials (oral dosing) [79,80]. The epimeric podophyllotoxin 35 (PPT), a cytotoxic agent known for its potent antimitotic activity, is also reported to be an IGF-1R selective substrate inhibitor. Both 34 and 35 are reported to inhibit IGF-1R catalyzed substrate phosphorylation of pGT with an IC50 value of 6 nM. Antiproliferative IC50 values against 11 cell lines for both compounds are between 20 nM and 25 nM. In preclinical models, 34 is efficacious when dosed intraperitoneally in a wide range of tumor models such as breast, prostate, malignant melanoma, and multiple myeloma. Results from cell culture studies using IGF-1R-deficient cell lines, mouse embryonic fibroblasts (MEFs), and HepG2 cells have called into question whether the observed antitumor activity is due to IGF-1R inhibition [81,82]. OH

OH

O

O O

O

O O

O

H3CO

OCH3

O

H3CO

OCH3

OCH3

OCH3

34

35

5. CONCLUSIONS Significant progress has been made in developing small molecule inhibitors of IGF-1R for use in the clinic. Coupled with the advances being made toward exploiting and validating the IGF-1R target using mAbs, the stage is set to determine the clinical potential of IGF-1R inhibitors. It will be interesting to follow the clinical development of molecules such as AXL-1717, BMS-754807, INSM-18, OSI-906, and XL-228 with respect to efficacy, safety, and tolerability. The hope remains that small molecule inhibitors will provide a complementary approach to mAb therapeutics in terms of efficacy and dosing flexibility, particularly, in combination studies with cytotoxics and EGFR antagonists.

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[28]

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