Therapeutic potential of selective histone deacetylase 3 inhibition

Accepted Manuscript Therapeutic potential of selective histone deacetylase 3 inhibition Lihui Zhang, Yiming Chen, Qixiao Jiang, Weiguo Song, Lei Zhang PII:

S0223-5234(18)30917-6

DOI:

https://doi.org/10.1016/j.ejmech.2018.10.072

Reference:

EJMECH 10896

To appear in:

European Journal of Medicinal Chemistry

Received Date: 26 September 2018 Revised Date:

18 October 2018

Accepted Date: 19 October 2018

Please cite this article as: L. Zhang, Y. Chen, Q. Jiang, W. Song, L. Zhang, Therapeutic potential of selective histone deacetylase 3 inhibition, European Journal of Medicinal Chemistry (2018), doi: https:// doi.org/10.1016/j.ejmech.2018.10.072. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The current knowledges about the prospects of selective inhibition of HDAC3 for the drug development were reviewed.

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Title Page Therapeutic Potential of Selective Histone Deacetylase 3 Inhibition Lihui Zhanga, Yiming Chenb, Qixiao Jiangc, Weiguo Songb and Lei Zhangb* a

School of Stomatology, Weifang Medical University, Weifang, Shandong, China; Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China; c

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School of Pharmacy, Qingdao University, Qingdao, Shandong, China.

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Author for correspondence: Tel./fax: +86-536-8462014 E-mail: [email protected]

Acknowledgement

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Some of the materials in this work were supported by National Natural Science Foundation of China (Youth Found, Grant No. 81803343).

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Therapeutic Potential of Selective Histone Deacetylase 3 Inhibition

Abstract

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Histone deacetylases (HDACs) are closely related to the occurrence and development of a variety of diseases, such as tumor, inflammation, diabetes mellitus, cardiovascular and neurodegenerative diseases. Inhibition of HDACs by developing HDAC inhibitors has achieved significant progress in the treatment of diseases caused by epigenetic abnormalities, and especially in the cancer therapy. Isoform selective HDAC inhibitors are emphasized to be disease specific and have less off-target effects and better safety performances. HDAC3 has been illustrated to play specific role in the development of several diseases, and the discovery of HDAC3 selective inhibitors has exhibited potential in the targeted disease treatment. Herein, we summarize the current knowledge about the prospects of selective inhibition of HDAC3 for the drug development. Keywords: HDAC3 selective inhibitor, tumor, diabetes, cardiovascular disease, inflammation, neurodegenerative disease. 1. Introduction

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Histone deacetylases (HDACs) are a group of enzymes that are responsible for the deacetylation of histone proteins, as well as more than 50 nonhistone proteins.[1-3] A total number of 18 different isoforms of HDACs which were divided into 4 classes have been identified in human.[4] HDAC1, 2, 3 and 8 are categorized as Class I HDACs which exist in the nucleus; While HDAC3 also locates in the cytoplasm. Class II HDACs shuttling between the cytoplasm and the nucleus are subdivided into IIa (HDAC4, 5, 7 and 9) and IIb (HDAC6 and 10). Class III HDACs including 7 NAD+ dependent enzymes are known as sirtuins. HDAC11 is classified as class IV for its low homology to other HDACs. In contrast with class III, class I, II and IV HDACs are zinc dependent HDACs which require zinc ions as cofactors. HDACs and histone acetyltransferases (HATs) regulate the acetylation level of histone and nonhistone proteins in an opposite manner.[5-7] The epigenetic acetylation adjustment plays important role in the regulation of cellular physiological functions, such as signal transduction, cell cycle, proliferation, apoptosis, cardiac development, and so on.[8-10] The over-expression and aberrant recruitment of HDACs is associated with tumor[11], diabetes mellitus[12], neurodegenerative diseases[13, 14], inflammatory disorders[15], HIV[16-18], and cardiac diseases[19, 20]. Pharmacological inhibition of HDACs results in increased acetylation levels of histones, and nonhistone proteins including tumor suppressors[21-23], signaling mediators[24, 25], nuclear factors[26, 27], 2

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transcription factors [28, 29] and DNA-repair proteins[30]. The subsequent modulated DNA transcriptions and altered cellular functions provide basis for the treatment of a variety of diseases.

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Discovery of HDAC inhibitors (HDACIs) was stimulated by the therapeutic prospect of HDAC inhibition. Development and utilization of HDACIs have been closely studied for more than 20 years. Significant achievements have been obtained in the development of HDACIs for treatment of epigenetic disorders, especially cancer[11]. Suberoylanilide hydroxamic acid (SAHA, 1) [31] and FK228 (2) [32] have been approved by US Food and Drug Administration (FDA) for treatment of refractory cutaneous T-cell lymphoma (CTCL, Figure 1). PDX101 (3) [33] and LBH589 (4) [34] were approved for the treatment of peripheral T-cell lymphoma (PTCL) and multiple myeloma, respectively. Chidamide (5) [35] is a benzamide HDACI approved by Chinese Food and Drug Administration (CFDA) for the treatment of relapsed or refractory PTCL in 2015. There are also more than 15 HDACIs evaluated in clinical investigations for the treatment of tumor and other diseases (http://www.clinicaltrials.gov).

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Most of the HDACIs approve by FDA or investigated in clinical trials are pan inhibitors or class selective inhibitors. Although HDACIs with low selectivity exhibited high activities in the preclinical or clinical studies, the side effects caused by the low selectivity are also concerning.[4, 36] Adverse events of pan HDACIs including the gastrointestinal nausea, vomiting, and anorexia, the constitutional fatigue, the hematologic thrombocytopenia, neutropenia, and anemia, the cardiac ECG changes, arrhythmias and prolongation of QT interval, and the metabolic liver toxicities, electrolyte imbalances, and renal dysfunction.[37] Single isoform selective inhibitors are regarded to have a safer and more specific role in the treatment of a certain disorder than the mixed isoform selective inhibitors. Therefore, discovery of specific isoform selective inhibitors has attracted wide interests in the development of HDACIs.

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Among the HDAC family members, HDAC3 is unique for its expression in the nucleus, cytoplasm, or membrane. HDAC3 deacetylates histone and non-histone proteins such as NF-kB[38], myocyte enhancer factor 2[39], and Src kinase[40]. Furthermore, recent studies have indicated that specific inhibition of HDAC3, is associated with the treatment of several diseases including cancer[41], inflammation[42], metabolic diseases[43] and neurodegenerative disorders[44]. Therefore, HDAC3 selective inhibitors are of great interest not only as tools for probing the biological functions of HDAC3, but also as candidate therapeutic agents with potentially few side effects. Several HDAC3 selective inhibitors have been discovered and evaluated in the activity assays for the treatment of a specific disease (Figure 2).[45-47] Herein, evidences that selective HDAC3 inhibition may be an effective strategy for treating certain diseases are reviewed. 3

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2. HDAC3 inhibition and disease treatment 2.1. Tumor

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HDACs have been shown to be aberrantly recruited in tumor cells, and expression of individual isoforms is often altered in a number of cancer types.[48] A single isoform of HDACs also plays a specific role in the pathogenesis of tumor. Therefore, selective inhibition of a single subtype of HDACs is considered to be promising in cancer treatment by targeting a particular tumor type or a specific mechanism in the tumorigenesis. Compared with pan HDACIs, the isoform selective inhibitors may have the advantage of functional specificity, high safety, and significant therapeutic outcomes.

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MicroRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs that are involved in the normal functioning of eukaryotic cells.[49] Expression of miRNAs is regulated by functional proteins and dysregulation of miRNAs is associated with many human diseases, particularly tumor.[50] MiR-195 frequently downregulated in various types of tumor, is a miRNA that can promote tumor cell apoptosis and suppress tumor cell proliferation, angiogenesis and metastasis by inhibiting the expression of target genes.[51, 52] Recently, Zhuang and coworkers revealed the roles of HDAC3 in the regulation of miR-195 in hepatocellular carcinoma (HCC).[53] Their findings showed that miR-195 transcription could be transactivated by Sp1 which directly binds to the promoter of miR-195 gene. HDAC3 inhibited the Sp1-induced miR-195 expression in HCC cells by deacetylation of histones bound to the miR-195 promoter. Knockdown of HDAC3, but not HDAC1 or HDAC2, remarkably enhanced miR-195 level. Inverse correlation between HDAC3 and miR-195 levels in HCC tissues was also explored by immunoblotting assays. The results suggest that selective inhibition of HDAC3, which is aberrantly activated in HCC, is promising in the treatment of HCC via transcriptional activation of miR-195.

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CHD5 belongs to a group of SWI/SNF proteins known as chromodomain helicase DNA binding (CHD) proteins, which was demonstrated as a tumor suppressor gene in various types of tumors, including gastric cancer (GC).[54] Zhang and coworkers identified that HDAC3 gene is the most significantly upregulated gene in GC tissues, and both HDAC3 mRNA and protein expression is upregulated in human GC tissues and cells.[55] In the GC tumor xenograft mouse model and colony formation assay, HDAC3 knockdown markedly decreased tumor weights and attenuated the colony formation capacity of GC cells. Microarray analysis revealed that the miR-454 level significantly and positively correlated with the HDAC3 level in GC tissues, indicating that HDAC3 overexpression upregulates miR-454 expression in GC. MiR-454 functioned as an oncogene by inhibiting CHD5 which downregulated in GC. Moreover, it is revealed that patients with a low expression of CHD5 had a markedly worse survival percentage compared to those 4

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with a high CHD5 level. Therefore, downregulation of MiR-454, and upregulation of CHD5 by inhibition of HDAC3 could be an attractive strategy for the treatment of GC.

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Studies based on a genetic animal model revealed the specific role of HDAC3 in the smoking-induced pancreatic cancer.[56] It is found that the smoking compounds significantly increase the phosphorylation level of HDAC3 and the translocation of phosphorylated HDAC3 to the nucleus. Molecular inhibition of HDAC3 decrease the level of IL-6 produced by the cancer cells, which plays an important role in mediating the interaction between cancer cells and macrophages. Therefore, inhibition of HDAC3 could be utilized in the cancer therapy by targeting novel mechanism of tumorigenesis. HDAC3 was also found specifically overexpressed in cholangiocarcinoma (CCA) tissues and correlated with reduced patient survival.[57] HDAC3 upregulation inhibited apoptosis and promoted CCA cell proliferation. Conversely, knockdown or pharmacological inhibition of HDAC3 exhibited decreased CCA cell growth and increased caspasedependent apoptosis. The results revealed that HDAC3 selective inhibition represent a novel treatment approach for CCA.

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Chemotherapy drugs are discovered to trigger upregulation of HDAC3 which inversely contributes to chemo-resistance.[58] HDAC3 promoted the phosphorylation and activation of AKT which specifically binds to HDAC3, but not other class I HDACs. Whereas HDAC3 depletion or inhibition reduced the association between AKT and HDAC3, and meanwhile sensitized leukemia cells to chemotoxicity-induced apoptosis. It is suggested that selective inhibition of HDAC3 may constitute a promising strategy to overcome chemotherapy resistance in AML treatment.

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Cancer stem cells (CSCs) theory is a recent concept about tumorigenesis. CSCs are a group of cells have the ability of self-renewal and differentiating into the heterogeneous nontumorigenic cancer cell types that in most cases appear to constitute the bulk of the cancer cells within the tumor.[59] It has been shown that high grade tumors are enriched with a high content of CSCs. Therefore, CSCs are considered to be the root of drug resistance, recurrence and metastasis of tumors. It has been discovered that HDAC3 participated in the self-renewal of liver CSCs through histone modification. Transcription factor Nanog[60] and CD133[61] have identified as markers for liver CSCs. Qian and coworkers found that expression of both HDAC3 and HDAC7 were higher in NanogPos cells than NanogNeg cell in the tested HCC cells.[62] However, only expression of HDAC3, and not HDAC7, was significantly correlated with both of Nanog and CD133 expression. HDAC3 expression was dramatically reduced in the NanogPos CSCs by knocked down of HDAC3. The results also shown suppressed sphere formation and clone formation, and dramatically reduced tumorigenicity of NanogPos CSCs after knockdown HDAC3 expression. Liver CSCs are resistant to 5

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therapeutic agent sorafenib in the previous study, however, HDAC3 inhibition could improve the sensitivity of liver CSCs to sorafenib revealed by Qian’s studies.

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Petukhov and coworkers investigated the effects of HDAC phosphorylation in breast cancer cells using a synthesized photoreactive probe.[63] HDAC3 was observed as single HDAC isoform exclusively engaged in triple-negative breast cancer (TNBC) cells. Moreover, increased HDAC3 phosphorylation was discovered in TNBC cells (MDAMB-231) compared with luminal subtypes (MCF-7, T47D and ZR75-1). Phosphorylation by c-Jun N-terminal kinase (JNK) is correlated with improved enzymatic activity and inhibitor binding of HDAC3 in TNBC cells in comparison with luminal cells. Moreover, it is demonstrated that HDAC3 regulate TNBC stem cells homeostasis by increasing βcatenin expression via activating the Akt/glycogen synthase kinase (GSK)3β signaling pathway.[64]

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It is demonstrated by Li and coworkers that molecule 6 (Figure 2) specifically decreases the expression of HDAC3, promotes the acetylation and transcriptional activity of p53, induces the expression of p21 and consequent cell cycle arrest of TNBC cells.[65] Colony formation can also be dramatically inhibited by administration of molecule 6 in both MDA-MB-231 and BT-20 cells. These results indicated the potential of selective inhibition of HDAC3 expression in the treatment of TNBC. HDAC3 selective inhibitor derived by structural modification of AR-42 exhibited in vitro efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of β-catenin.[64] Among the synthesized AR-42 derivatives, molecule 7 was designed by replacement of hydroxamic acid group and isopropyl group in AR-42 with N-(2-amino-4-fluorophenyl)amide group and dimethyl group, respectively. In the in vivo evaluation, molecule 7 also revealed suppressive effect on tumorigenesis in nude mice compared with knockdown of HDAC3. Therefore, selectively targeting HDAC3 and HDAC3 phosphorylation is of great prospects in the development of antitumor drugs for the treatment of TNBC.

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In discovery of Mocetinostat derivatives as potent HDACIs, a series of benzamide HDACIs were synthesized with an oxazoline capping group.[66] Among these Mocetinostat analogs, molecule 8 exhibited high HDAC3-NCoR2 inhibitory selectivity with IC50 value of 6 nM compared with IC50 values other HDACs (HDAC1: IC50 = 80 nM; HDAC2: IC50 = 110 nM; HDAC4, 5, 6, 7 and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 >2000 nM). In the activity evaluation, the tested HDAC3 selective inhibitors increased histone H3K9 acetylation levels in both human U937 and PC-3 cell lines. However, cyclin E expression in U937 cells but not in PC-3 cells was decreased by HDAC3 inhibitors, indicating underlying differences in the action mechanisms of HDAC3 inhibitors on those two cell lines. It is revealed that highly selective HDAC3 inhibitors could be derived by structural modification of existing HDACIs, and selective inhibition of HDAC3 may be used to 6

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target a specific mechanism in the tumor treatment. 2.2. Diabetic and cardiovascular diseases

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Inhibition of HDACs, particularly HDAC3, for the treatment of diabetes has been reviewed by Wagner and coworkers.[67] It is revealed that inhibition of HDAC3 promotes hepatic FGF21 expression, upregulates oxidative metabolism, regulates gluconeogenesis and protects pancreatic β-cell from cytokine-induced apoptosis. Selective HDAC3 inhibition showed beneficial for the treatment of both type 1 and type 2 diabetes.

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Peroxisome proliferator-activated receptor gamma (PPARγ) is a well-documented transcription factor that plays an important role in the regulation of glucose and fatty acid metabolism.[68] Insufficient PPARγ activity is associated with adipose tissue dysfunction and glucose disorders in metabolic syndrome.[69] Function of PPARγ is regulated by phosphorylation[70], sumoylation[71], ubiquitination[72], and especially acetylation modifications.[73, 74] It is revealed that PPARγ is repressed by binding to the corepressor formed by HDAC3 and silencing mediator for retinoid and thyroid hormone receptors (SMRT)/nuclear receptor corepressor (NCoR) in the absence of ligands.[75] Ligand binding of PPARγ leads to disassociation of the corepressor complex and induces recruitment of coactivators. Inhibition of HDAC3 is also of effective strategy for the activation of PPARγ.

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Gao and coworkers revealed that HDAC3 inhibition induced PPARγ acetylation and activation in the absence of exogenous ligands.[76] It is observed that RNAi-mediated knockdown of HDAC3 or HDAC3 inhibitor increased acetylation of the PPARγ protein, enhanced the expression of PPARγ target genes, and subsequent increased glucose uptake, activated insulin signaling, and enhanced lipid accumulation. The results suggest that acetylation of PPARγ is a ligand (thiazolidinediones, TZDs) independent mechanism of PPARγ activation. HDAC3 selective inhibitor (molecule 9) also exhibited potential of PPARγ activator and insulin sensitizer. It is indicated that selective inhibition of HDAC3 represent a new approach for improving insulin sensitivity in the treatment of type 2 diabetes without the side effects of synthetic PPARγ ligands. To date, type 1 diabetes is lack of effective therapies, promotion of β-cell survival using small molecules has been considered as a critical strategy to maintain β-cell functions.[77, 78] It is exhibited that HDACs regulate inflammatory gene expression, and inhibition of HDACs reveals anti-inflammatory activities.[79] BRD3308 (10), a HDAC3 selective inhibitor, has been discovered to suppress β-cell apoptosis induced by inflammatory cytokines or glucolipotoxic stress, and increase insulin secretion in vitro.[80] In addition, improper hematopoietic stem cell maintenance, defects in T-cell maturation and NKT cell 7

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development have been induced by tissue-specific deletion of HDAC3. An in vivo study showed that daily treatment of BRD3308 leads to a reduced inflammation phenotype allowing β-cells to proliferate in compensation, protects β-cells from apoptosis by preventing pancreatic islets from mononuclear immune cell infiltration, and slows aggressive disease progression.[81] These results suggested that selective inhibition of HDAC3 by small molecules, exhibited potential of delaying the progression of autoimmune type 1 diabetes by resetting of the immune system from a destructive to a protective phenotype.

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Diabetic cardiomyopathy (DCM) is cardiac complications of diabetes characterized by myocardial disorders without coronary artery disease.[82] Activation of HDACs has been discovered to be associated with the pathogenesis of DCM.[83, 84] Thus, inhibition of HDACs may be effective method in the treatment of DCM. The role of HDAC3 inhibition has been studied by Cai and coworkers in the OVE26 diabetic mice model.[85] The results displayed that specific HDAC3 inhibition by RGFP966 (11), protects the diabetic mice against diabetes-induced cardiac dysfunction and remodeling. The protective effect by HDAC3 inhibition was persistent even until 3 months after the end of treatment. It is indicated that the cardioprotective effects by inhibition of HDAC3 is mediated by acetylation of histone H3 on the DUSP5 gene promoter, increased expression of DUSP5, and subsequent suppression of the ERK1/2 signaling. The results suggested that HDAC3 present an important target for the prevention of DCM in Type 1 diabetic patients, and HDAC3 selective inhibitors could be potentially used in the cardioprotective therapies against diabetes-induced cardiac diseases.

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It is also exhibited that the HDAC3 inhibitor RGFP966 prevents diabetes-induced aortic pathologies by decreasing hepatic kelch-like ECH-associated protein 1 (Keap1) levels, increasing miR-200a levels and erythroid 2-related factor 2 (Nrf2) nuclear translocation, and subsequent activation of multiple antioxidative and anti-inflammatory genes.[86] The expression heart and aorta protective fibroblast growth factor 21 (FGF21) was increased by HDAC3 inhibition, leading to an promotion in the repair of diabetes-induced aorta damage. Collectively, HDAC3 inhibition is demonstrated to be promising in the clinical prevention of multiple diabetic complications, including aortic disorders. Atherosclerosis is a lipid-driven chronic inflammatory disease, and macrophages as the key immune cells in atherosclerotic plaques play a significant role in disease progression.[87] Epigenetic remodeling of histones regulates macrophages and their inflammatory repertoire.[88] Particularly, regulation of histone acetylation status by HDACs is essential in innate immune responses, and affects the atherosclerosis development.[42, 89] Winther and coworker revealed the role of HDAC3 in the adjustment of macrophage phenotype, collagen deposition, plaque phenotype and profibrotic TGFB1 expression.[90] Due to enhanced collagen deposition, the Hdac3del mice 8

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showed a favorable plaque phenotype featured by improved stability and increased plaque size. Hdac3del macrophage exhibited increased expression and production of antiatherosclerotic cytokine Tgfb1, and resulted in stimulated production of collagen by VSMCs. Moreover, the plaque showed features of reduced lipid accumulation and a shift in macrophage phenotype toward an anti-inflammatory pro-fibrotic gene program, which were attributable to myeloid Hdac3 deletion. The authors also discovered that HDAC3 which targets the Tgfb1 locus, was the sole HDAC upregulated in human ruptured plaques. The HDAC3 expression in human ruptured atherosclerotic lesions was positively correlated with activated macrophage marker CD68, CD86 and HLA-DPB1 mRNA expression, and inversely correlated with plaque-stabilizing TGFB1 gene expression. Due to the important role of HDAC3 in the development of atherosclerosis, selective inhibition of HDAC3 is prospective in the discovery of anti-atherosclerotic drugs.

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Inflammation is a protective response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, normally, the generic response is beneficial for homeostasis restoration and tissue repair by means of clearing pathogens and harmful cell components.[91] However, excessive inflammation may lead to diseases, such as the progression of neurological diseases triggered by microglia activation.[92] Recently, inhibition of HDACs has been reported in the regulation of innate immune activity.[93, 94] Zhang and coworkers have shown that HDAC3 selective inhibitor RGFP966 downregulates TLR signaling pathway, STAT3/5 pathway, microglia activation and inflammatory response in central nervous system.[95] Compared with knockdown of HDAC3 and pan HDACIs, HDAC3 selective inhibitor exhibited therapeutic potential in the treatment of neurological diseases by repression of inflammatory response.

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Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by progressive destruction of inflamed joints.[96] Inhibition of HDACs has been shown to have potential in the treatment of RA, through both anti-inflammatory and anti-proliferative mechanisms.[97, 98] It is revealed that peripheral blood mononuclear cells (PBMCs) from RA patients exhibit greater HDAC activity than those from healthy subjects. TSA as a non-selective HDACI, was discovered to repress the production of interleukin-6 (IL-6) in both RA and healthy PBMCs, and also inhibit the release of interferon-γ (IFNγ, not produced by RA PBMCs) in healthy PBMCs.[99] However, the HDAC3 selective inhibitor MI192 (12), inhibited IL-6 production in RA PBMCs but not healthy PBMCs. The results indicated the advantage of selective HDACIs characterized by specific functions in the RA treatment. It is suggested that increased HDAC activity is related to RA pathogenesis, selective inhibition of HDAC3 represent a novel treatment approach for RA with reliable safety. 9

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2.4. Huntington’s disease

3. Discussion and Perspective

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Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction, cognitive deficits and psychiatric disturbances.[100] Some of the HD symptoms can be managed by currently available treatments, but the disease progress still could not be reversed or slowed. Before onset of motor symptoms, HD patients and mice were discovered to show significant declines in cognitive function.[101, 102] Notably, it is revealed that HDAC3 downregulates gene expression required for long-term memory formation, and focal deletion or selective inhibition of HDAC3 improves memory and neural plasticity.[103, 104] It is demonstrated that early intervention in HdhQ7/Q111 knock-in mice with RGFP966, a selective HDAC3 inhibitor, prevents deficits in motor learning and long-term memory, reduces striatal CAG repeat expansions and improves hippocampal and striatal pathologies.[105] Combined with beneficial effects of HDAC3 inhibition on motor function, the results indicate that selective HDAC3 inhibition simultaneously delivers multiple benefits in HD mice. Therefore, HDAC3 is an attractive therapeutic target in the HD treatment by inhibiting striatal expansions and delaying the disease progress.

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HDACs are a family of enzymes which may make similar contributions in the disease development. During past years, studies have revealed specific roles of single isoform of HDACs in the onset and progression of some diseases. Development of pan HDAC inhibitors has achieved major progress with the launch of SAHA, PDX101 and LBH589. The isoform selective HDACIs receiving great attention in the drug development, are regarded to have more specific function and less side effects. The FDA approved FK228 and CFDA approved Chidamide are not isoform selective inhibitors in strict significance, because they exhibited unobvious selectivity among HDAC1, 2 and 3. Currently, the approval and clinical application of isoform selective HDACIs is still a great challenge.

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HDAC3 is the sole HDAC binding to the nuclear receptor corepressor NCOR1/SMRT in cell nucleus. Thus, HDAC3 unlike other HDACs, has a unique role in modulating the transcriptional activities of nuclear receptors. It has been revealed that HDAC3 is involved in specific mechanisms in the emerging and development of tumor, diabetes mellitus, inflammation, cardiovascular and neurodegenerative diseases. Therefore, targeting a unique mechanism in the disease progress by selective inhibition of HDAC3 results in more precise and safer therapies compared with the pan HDACIs. Several HDAC3 selective inhibitors have exhibited potential in the treatment of cancer, diabetes and diabetic complications. With in-depth knowledge of HDAC3 and development of discovery technologies, the process of brought HDAC3 selective inhibitors to market will be significantly accelerated. Nevertheless, safety characteristics of HDAC3 selective 10

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inhibitors are of special concern. HDAC3 deletion has been shown to induce massive cardiac hypertrophy and global deletion of HDAC3 resulted in lethality by E9.5. Therefore, specificity of cells or tissues is necessary to be evaluated in the development of HDAC3 selectivity inhibitors.[106]

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One major barrier in the development of HDAC3 selective inhibitors is the high structural similarity among HDAC1, 2 and 3. HDAC3 shares high sequence identities with HDAC1 (sequence identity = 62.0%, sequence similarity = 81.4%) and HDAC2 (sequence identity = 62.6%, sequence similarity = 82.9%) revealed by sequence alignment (Figure 3). Moreover, residues in the active site are demonstrated to be more conservative than amino acids in other regions. Structural analysis suggested that HDAC3 selectivity could be adjusted by targeting residues in the opening of the active site.[107] Therefore, HDAC3 selective inhibitors may be derived by carefully designed cap regions in HDACIs. The existed HDAC3 inhibitors are also valuable resources for the ligand based design of HDAC3 selective inhibitors. Selectivity of current HDAC3 selective inhibitors could be elucidated by their conformations and interactions in the active site of different HDAC isoforms using accurate and reliable computational methods such as molecular dynamic simulation and quantum algorithm. The virtual screening approach considering structures of both HDAC3 and its selective ligand could be an efficient way in the rapid discovery of HDAC3 selective inhibitors. With the increasing knowledge of therapeutic potential by the inhibition of HDAC3, discovery of HDAC3 selective inhibitors will attract widespread interest in the field of drug development.

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Novel mechanisms of HDA3 inhibition demonstrated in the treatment of diseases, indicate the specificity and safety characteristics of HDAC3 selective inhibitors. Several HDAC3 inhibitors have been discovered, which exhibited high selectivity for HDAC3 over HDAC1, 2 and other HDACs. Among them, RGFP966 exhibited potential in the treatment in the treatment of tumor, diabetes-induced cardiomyopathy and aortic pathologies, inflammation and Huntington’s disease. In the treatment of cancer, molecule 6, 7 and 8 were demonstrated to play a specific role. Molecule 9 functioned as a PPARγ activator in the treatment type 2 diabetes; BRD3308 inhibited the process of type 1 diabetes by resetting of the immune system; MI192 showed RA inhibitory potency by inhibition of IL-6 production. With the increasing number of HDAC3 selective inhibitor derived, significant progress would be achieved in the prevention and treatment of diseases by extensive studies of HDAC3 inhibitors. Development and application of HDAC3 selective inhibitors are also conductive to the precise and personalized therapies against epigenetic abnormality diseases. References 11

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Figure captions Figure 1 HDAC inhibitors approved by US FDA and CFDA.

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Figure 2 Novel HDAC3 selective inhibitors.

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Figure 3 Sequence alignment of HDAC3 to HDAC1 and HDAC2 plotted by the ESPript 3.0 program.[108]

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ACCEPTED MANUSCRIPT Highlights 1. Isoform selective HDAC inhibitors are regarded to have reduced adverse effects. 2. HDAC3 is the sole HDAC binding to the nuclear receptor corepressor NCOR1/SMRT in cell nucleus.

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3. HDAC3 plays a specific role in tumor development, cancer stem cell renewal, and the pathogeny of other diseases. 4. Selective inhibition of HDAC3 is of huge therapeutic potential for the disease treatment by targeting novel mechanisms.

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5. Development of HDAC3 selective inhibitors is promising in the drug discovery.