Isoform-selective Histone Deacetylase Inhibitors Research Articles

Stack-HDAC3i: A high-precision identification of HDAC3 inhibitors by exploiting a stacked ensemble-learning framework

Epigenetics involves reversible modifications in gene expression without altering the genetic code itself. Among these modifications, histone deacetylases (HDACs) play a key role by removing acetyl groups from lysine residues on histones. Overexpression of HDACs is linked to the proliferation and survival of tumor cells. To combat this, HDAC inhibitors (HDACi) are commonly used in cancer treatments. However, pan-HDAC inhibition can lead to numerous side effects. Therefore, isoform-selective HDAC inhibitors, such as HDAC3i, could be advantageous for treating various medical conditions while minimizing off-target effects. To date, computational approaches that use only the SMILES notation without any experimental evidence have become increasingly popular and necessary for the initial discovery of novel potential therapeutic drugs. In this study, we develop an innovative and high-precision stacked-ensemble framework, called Stack-HDAC3i, which can directly identify HDAC3i using only the SMILES notation. Using an up-to-date benchmark dataset, we first employed both molecular descriptors and Mol2Vec embeddings to generate feature representations that cover multi-view information embedded in HDAC3i, such as structural and contextual information. Subsequently, these feature representations were used to train baseline models using nine popular ML algorithms. Finally, the probabilistic features derived from the selected baseline models were fused to construct the final stacked model. Both cross-validation and independent tests showed that Stack-HDAC3i is a high-accuracy prediction model with great generalization ability for identifying HDAC3i. Furthermore, in the independent test, Stack-HDAC3i achieved an accuracy of 0.926 and Matthew’s correlation coefficient of 0.850, which are 0.44–6.11% and 0.83–11.90% higher than its constituent baseline models, respectively.

Dual-targeting class I HDAC inhibitor and ATM activator, SP-1-303, preferentially inhibits estrogen receptor positive breast cancer cell growth.

Dual-targeting chromatin regulation and DNA damage repair signaling presents a promising avenue for cancer therapy. Applying rational drug design, we synthesized a potent dual-targeting small molecule, SP-1-303. Here, we report SP-1-303 as a class I isoform selective histone deacetylase (HDAC) inhibitor and an activator of the ataxia-telangiectasia mutated protein (ATM). In vitro enzymatic assays demonstrated selective inhibition of HDAC1 and HDAC3. Cellular growth inhibition studies show that SP-1-303 differentially inhibits growth of estrogen receptor positive breast cancer (ER+ BC) cells with effective growth inhibition concentrations (EC50) for MCF-7 and T47D cells ranging from 0.32 to 0.34 μM, compared to 1.2-2.5 μM for triple negative breast cancer cells, and ~12 μM for normal breast epithelial cells. Western analysis reveals that SP-1-303 decreases estrogen receptor alpha (ER-α) expression and increases p53 protein expression, while inducing the phosphorylation of ATM and its substrates, BRCA1 and p53, in a time-dependent manner in ER+ BC cells. Pharmacokinetic evaluation demonstrates an area under the curve (AUC) of 5227.55 ng/ml × h with an elimination half-life of 1.26 h following intravenous administration in a rat model. Collectively, SP-1-303 emerges as a novel second generation class I (HDAC1 and HDAC3) selective HDAC inhibitor, and ATM activator, capable of modulating ER expression, and inhibiting growth of ER+ BC cells. Combined targeting of class I HDACs and ATM by SP-1-303 offers a promising therapeutic approach for treating ER+ breast cancers and supports further preclinical evaluation.

Application of Ligand- and Structure-Based Prediction Models for the Design of Alkylhydrazide-Based HDAC3 Inhibitors as Novel Anti-Cancer Compounds.

Histone deacetylases (HDAC) represent promising epigenetic targets for several diseases including different cancer types. The HDAC inhibitors approved to date are pan-HDAC inhibitors and most show a poor selectivity profile, side effects, and in particular hydroxamic-acid-based inhibitors lack good pharmacokinetic profiles. Therefore, the development of isoform-selective non-hydroxamic acid HDAC inhibitors is a highly regarded field in medicinal chemistry. In this study, we analyzed different ligand-based and structure-based drug design techniques to predict the binding mode and inhibitory activity of recently developed alkylhydrazide HDAC inhibitors. Alkylhydrazides have recently attracted more attention as they have shown promising effects in various cancer cell lines. In this work, pharmacophore models and atom-based quantitative structure-activity relationship (QSAR) models were generated and evaluated. The binding mode of the studied compounds was determined using molecular docking as well as molecular dynamics simulations and compared with known crystal structures. Calculated free energies of binding were also considered to generate QSAR models. The created models show a good explanation of in vitro data and were used to develop novel HDAC3 inhibitors.

Trapoxin A Analogue as a Selective Nanomolar Inhibitor of HDAC11

Histone deacetylases (HDACs) are enzymes that regulate many important biological pathways. There is a need for the development of isoform-selective HDAC inhibitors for further biological applications. Here, we report the development of trapoxin A analogues as potent and selective inhibitors of HDAC11, an enzyme that can efficiently remove long-chain fatty acyl groups from proteins. In particular, we show that one of the trapoxin A analogues, TD034, has nanomolar potency in enzymatic assays. We show that in cells, TD034 is active at low micromolar concentrations and inhibits the defatty acylation of SHMT2, a known HDAC11 substrate. The high potency and selectivity of TD034 would permit further development of HDAC11 inhibitors for biological and therapeutic applications.

Current HDAC Inhibitors in Clinical Trials

Epigenetic modifications in eukaryotic biological pathways can lead to the up- or downregulation of regulatory proteins contributing to disease onset and progression. In the last three decades, histone deacetylases (HDACs) are among the most studied epigenetic targets. In fact, aberrant HDAC expression is associated with numerous types of cancer and neurodegenerative disorders, making HDACs promising molecular targets for the design of new drugs. Many HDAC inhibitors (HDACi) are currently in clinical evaluation for various types of cancer, and some of them reached the market after approval by the Food and Drug Administration (FDA). The present review summarizes the various HDAC classes and relative isoforms. Then we discuss different class or isoform-selective HDACi with a strong emphasis on late-stage preclinical candidates and drugs in clinical studies. Last but not least, we shed light on the pharmacokinetic challenges and future directions in HDACi design.

Discovery of Potent and Isoform-selective Histone Deacetylase Inhibitors Using Structure-based Virtual Screening and Biological Evaluation.

Histone deacetylases (HDACs) are key enzymes in epigenetics and promising targets for anticancer therapy. Although several drugs targeting HDAC have been approved for the treatment of tumors, their clinical use has been limited by their deleterious side effects and poor efficacy. Herein, we discover four potent HDAC inhibitors through pharmacophore model screening and molecular docking. These compounds are able to bind HDACs 1, 3, and 6 with nanomolar affinity. Among them, compound 3 shows greater inhibitory effect on HDACs 1, 3, and 6 than that of vorinostat (SAHA). Evaluation of anticancer activity indicates that compound 3 significantly inhibits the growth of solid cancer cells including HGC-27, AGS, MDA-MB-231, A549, MCF-7, and H460 cells. In vivo anticancer study suggests that compound 3 can also markedly inhibit the growth of HGC-27 cells-derived xenograft, with no observable toxicity. These findings suggest that compound 3 may be as a potential HDAC-targeting inhibitor for solid tumor therapy.

MS275 as Class I HDAC inhibitor displayed therapeutic potential on malignant ascites by iTRAQ-based quantitative proteomic analysis

BackgroundMalignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity. Epigenetic modulators play a key role in cancer initiation and progression, among which histone deacetylases (HDACs) are considered as one of the most important regulators for various cancer development, such as liver cancer, ovarian cancer, and pancreatic cancer et al. Thus, in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites.MethodsIn this report, we tested the therapeutic effect of different isoform selective HDAC inhibitors (Class I HDACI MS275, Class IIa HDACI MC1568, pan-HDAC inhibitors SAHA) on malignant ascites in vitro and in vivo. We further used proteome analysis to find the potential mechanisms for malignant ascites therapy.ResultsAmong the different isoform-selective HDAC inhibitors, the class I selective HDACI, MS275, exhibited preferential inhibition on various ascites cells. MS275 could induce cell cycle arrest in G0/G1 phase and promote apoptosis on ascites cells. Through proteome analysis, we found MS275 could downregulate proteins related to cell cycle progression, such as CDK4, CDC20, CCND1; MS275 could upregulate pro-apoptosis proteins such as PAPR1, LMNB2 and AIFM1; in addition, MS275 could change the expression of tumorigenic proteins related to the specific malignant ascites bearing tumors, such as TSP1 and CDK4 for bladder cancer. We then confirmed that abemaciclib (CDK4/6 selective inhibitor) could inhibit the proliferation of ascites cells, and the combination of abemaciclib and MS275 had synergistic anti-tumor effect. Finally, we found that MS275 could in vivo inhibit malignant ascites progression (ascites volume: 2.9 ± 1.0 mL vs 7.5 ± 1.2 mL, p < 0.01), tumor growth, and prolong 66% of the life-span when compared with the untreated group.ConclusionThis present research revealed that the class I selective HDAC inhibitor, MS275, could effectively inhibit malignant ascites development and tumor growth via multiple pathways. These results indicated that HDACI could have great potential for clinical therapy of malignant ascites.

Rational Design and Development of HDAC Inhibitors for Breast Cancer Treatment

Breast cancer is the most prevalent cancer amongst females across the globe, and with over 2 million new cases reported in 2018, it poses a huge economic burden to the already dwindling public health. A dearth of therapies in the pipeline to treat triple-negative breast cancers and acquisition of resistance against the existing line of treatments urge the need to strategize novel therapeutics in order to add new drugs to the pipeline. HDAC inhibitors (HDACi) is one such class of small molecule inhibitors that target histone deacetylases to bring about chromosomal remodelling and normalize dysregulated gene expression that marks breast cancer progression. While four HDACi have been approved by the FDA for the treatment of different cancer types, no HDACi is specifically earmarked for clinical management of breast cancer. Owing to the differential HDAC expression pertaining to different types of breast cancers, isoform-selective HDAC inhibitors need to be discovered. This review attempts to set the stage for the rational structure-based discovery of isoform-selective HDACi by providing structural insights into different HDACs and their catalytic folds based on their classes and individual landscape. The development of inhibitors in accordance with the differential expression of HDAC isoforms exhibited in breast cancer cells is a promising strategy to rationally design selective and effective inhibitors, adopting a 'personalized-medicine' approach.

Structure-based virtual screening for novel potential selective inhibitors of class IIa histone deacetylases for cancer treatment

The fundamental cause of human cancer is strongly influenced by down- or up-regulations of epigenetic factors. Upregulated histone deacetylases (HDAC) have been shown to be effectively neutralized by the action of HDACs inhibitors (HDACi). However, cytotoxicity has been reported in normal cells because of non-specificity of several available HDACis that are in clinical use or at different phases of clinical trials. Because of the high amino acid sequence and structural similarity among HDAC enzymes, it is believed to be a challenging task to obtain isoform-selectivity. The essential aim of the present research work was to identify isoform-selective inhibitors against class IIa HDACs via structure-based drug design. Based on the highest binding affinity and isoform-selectivity, the top-ranked inhibitors were in silico tested for their absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties, which were classified as drug-like compounds. Later, molecular dynamics simulation (MD) was carried out for all compound-protein complexes to evaluate the structural stability and the biding mode of the inhibitors, which showed high stability throughout the 100 ns simulation. Free binding energy predictions by MM-PBSA method showed the high binding affinity of the identified compounds toward their respective targets. Hence, these inhibitors could be used as drug candidates or as lead compounds for more in silico or in vitro optimization to design safe isoform-selective HDACs inhibitors.

Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors

The discovery and development of isoform-selective histone deacetylase (HDAC) inhibitor is a challenging task because of the sequence homology among HDAC enzymes. In the present work, novel tetrahydro benzo[b]thiophene-3-carbonitrile based benzamides were designed, synthesized, and evaluated as HDAC inhibitors. Pharmacophore modeling was our main design strategy, and two novel series of tetrahydro benzo[b]thiophene-3-carbonitrile derivatives with piperidine linker (series 1) and piperazine linker (series 2) were identified as HDAC inhibitors. Among all the synthesised compounds, 9h with 4-(aminomethyl) piperidine linker and 14n with piperazine linker demonstrated good activity against human HDAC1 and HDAC6, respectively. Both the compounds also exhibited good antiproliferative activity against several human cancer cell lines. Both these compounds (9h and 14n) also induced cell cycle arrest and apoptosis in U937 and MDA-MB-231 cancer cells. Overall, for the first time, this research discovered potent isoform-selective HDAC inhibitors using cyclic linker instead of the aliphatic chain and aromatic ring system, which were reported in known HDAC inhibitors.

Abstract PO023: Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225

Abstract In addition to their canonical role in transcriptional regulation, Histone deacetylases (HDACs) regulate other cellular functions by maintaining a balance of lysine acetylation on key cellular proteins. HDAC inhibitors are under development for use in treating cancers, neurological, and immunological diseases. A barrier to the development of HDAC inhibitors has been the toxicity associated with non-selective pan-HDAC inhibitors, which simultaneously inhibit multiple HDAC isoforms. Isoform selective HDAC inhibitors offer disease targeting with an improved toxicity profile. HDAC6 presents an important target due to its role in immune regulatory processes involved in antitumor immune responses. We have shown that selective inhibition of HDAC6 regulates macrophages to recognize, phagocyte, and present antigens to the adaptive immune system. Treatment with our selective HDAC6 inhibitor, SP-2-225, was shown to enhance the production of cancer-associated antigens and macrophage antigen cross-presentation to T cells. Through a non-cytotoxic mechanism, SP-2-225 significantly reduced the tumor volume in a syngeneic SM1 melanoma model. Analysis of the tumors from treated animals showed a significant shift in the M1/M2 ratio of the infiltrating macrophages as compared to control, indicating that SP-2-225 caused a pro-inflammatory, antitumor shift in the macrophage equilibrium surrounding the tumor. This was identified as the putative mechanism through adoptive cell therapy where macrophages from naive animals were harvested and treated ex-vivo with SP-2-225. Reimplantation of these SP-2-225 ex-vivo treated macrophages resulted in reduced tumor volumes when compared to both vehicle and untreated macrophage animal cohorts. We propose that this selective inhibitor of HDAC6 offers potential as a stand-alone cancer therapy and in combination with other immunotherapies and radiation treatments. Citation Format: Scott Grindrod, Satish Noonepalle, Nima Aghdam, Alfredo Velena, Maria Gracia-Hernandez, Christian Zevallos-Delgado, Mira Jung, Anatoly Dritschilo, Alejandro Villagra. Immune-mediated tumor growth inhibition by selective HDAC6 inhibitor SP-2-225 [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO023.

Therapeutic effects of histone deacetylase inhibitors on heart disease.

A wide range of histone deacetylase (HDAC) inhibitors have been studied for their therapeutic potential because the excessive activity and expression of HDACs have been implicated in the pathogenesis of cardiac diseases. An increasing number of preclinical studies have demonstrated the cardioprotective effects of numerous HDAC inhibitors, suggesting a wide variety of mechanisms by which the inhibitors protect against cardiac stress, such as the suppression of cardiac fibrosis and fetal gene expression, enhancement of angiogenesis and mitochondrial biogenesis, prevention of electrical remodeling, and regulation of apoptosis, autophagy, and cell cycle arrest. For the development of isoform-selective HDAC inhibitors with high efficacy and low toxicity, it is important to identify and understand the mechanisms responsible for the effects of the inhibitors. This review highlights the preclinical effects of HDAC inhibitors that act against Zn2+-dependent HDACs and the underlying mechanisms of their protective effects against cardiac hypertrophy, hypertension, myocardial infarction, heart failure, and atrial fibrillation.

Discovery of N-(2-Amino-4-Fluorophenyl)-4-[bis-(2-Chloroethyl)-Amino]-Benzamide as a Potent HDAC3 Inhibitor.

In discovery of HDAC inhibitors with improved activity and selectivity, fluorine substitution was performed on our previously derived lead compound. The synthesized molecules N-(2-amino-4-fluorophenyl)-4-[bis-(2-chloroethyl)-amino]-benzamide (FNA) exhibited class I (HDAC1, 2, and 3) selectivity in the in vitro enzymatic assay and especially potent against HDAC3 activity (IC50: 95.48 nM). The results of in vitro antiproliferative assay indicated that FNA exhibited solid tumor cell inhibitory activities with IC50 value of 1.30 μM against HepG2 cells compared with SAHA (17.25 μM). Moreover, the in vivo xenograft model study revealed that FNA could inhibit tumor growth with tumor growth inhibition (TGI) of 48.89% compared with SAHA (TGI of 48.13%). Further HepG2 cell–based apoptosis and cell cycle studies showed that promotion of apoptosis and G2/M phase arrest make contributions to the antitumor activity of FNA. In addition, drug combination results showed that 0.5 μM of FNA could improve the anticancer activity of taxol and camptothecin. The present studies revealed the potential of FNA utilized as a high potent lead compound for further discovery of isoform selective HDAC inhibitors.

Recent progress on HDAC inhibitors with dual targeting capabilities for cancer treatment.

Histone deacetylases (HDACs) are a class of enzymes that remove acetyl from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis. As a result, HDACs represent an excellent target for anti-cancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified in the last decade with numerous HDACis being discovered, and some of them have reached the market. However, currently available HDACis are mostly non-isoform selective and suffer from several drawbacks such as limited efficacy, drug resistance, and toxicities. Therefore, isoform-selective HDACis and HDACis with dual targeting capabilities have attracted much attention from academia to industry in the past 5 years, and great advances have been achieved in this area. In this paper, we summarize recent progress on HDACis with dual targeting capabilities and their potential application to cancer treatment.

Isoform-specific characterization of class I histone deacetylases and their therapeutic modulation in pulmonary hypertension

Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circumvent off-target effects.

Pharmacophore-enabled virtual screening, molecular docking and molecular dynamics studies for identification of potent and selective histone deacetylase 8 inhibitors

Histone deacetylases (HDACs) play important roles in various biological processes, but are also notorious for their over-expression in numerous cancers and neurological disorders. Therefore, the development of isoform selective HDAC inhibitors is crucial in order to prevent any side effects of pan inhibition. This work focuses on identifying novel inhibitors for the selective inhibition of HDAC8, an isoform implicated in fatal diseases like T-cell lymphoma, colon cancer and childhood neuroblastoma. Virtual screening of the ‘In-trials’ subset of ZINC database has been carried out with the help of two pharmacophore models signifying potent and selective HDAC8 inhibition. A detailed molecular docking strategy, followed by molecular dynamics simulations and post-scoring with MM-GBSA calculations, has led to the identification of six promising molecules that have excellent binding with the HDAC8 active site. In order to establish the selectivity profile of these molecules, their binding to off-target HDAC isoforms has also been evaluated. Substitution analyses of the proposed inhibitors suggest that aromatic substituents that access the adjacent hydrophobic pocket of the HDAC8 active site have the potential to further enhance the HDAC8 selectivity.

Exploring structural requirements of isoform selective histone deacetylase inhibitors: a comparative in silico study

Histone deacetylases (HDACs) are a widely popular class of epigenetic regulators, second only in importance to DNA methyltransferases. They are responsible for deacetylating the lysine residues of a wide range of proteins, both nuclear and cytoplasmic. Therefore, deregulated HDAC activity is implicated in disruption of important biological functions leading to cancerous, neuropathological, infectious and inflammatory diseased states. The current therapeutic strategies aimed at combating HDAC related pathologies consist of pan HDAC inhibitors that target multiple HDAC isoforms. Many side-effects of such therapeutics have been reported due to off-target effects. Hence, efforts need to be focused towards developing therapeutics targeting single isoforms. This work aims at recognizing structural features, both of receptors and inhibitors, that would help achieve selective inhibition of HDAC isoforms. Protein alignment studies have been carried out to define the receptor structure differences that can be exploited for this purpose. Binding modes of highly isoform selective inhibitors have been established through molecular docking studies to characterize the receptor-ligand interactions responsible for selective inhibition. This information is represented with the help of pharmacophore models.

Design, Synthesis and In Vitro Biological Evaluation Of N-(2-Aminophenyl)-3-Quinolin-4-yl -Prop-2-enamide Derivatives As Novel Colon Anticancer Agents

Acetylation and deacetylation of histone proteins is regulated through two enzymes; acetylation is mediated through histone acetyl transferase (HAT) whereas deacetylation is mediated through histone deacetylase (HDAC). Histone deacetylase removes acetyl group of lysine residue on histone proteinthis makes negatively charged histone able to bind with DNA containing positive centers. In this way DNA remain in compact form with histone proteins. Therefore the transcription or replication enzymes and cofactors not able to bind such compact DNA structure. Histone deacetylase inhibition results into inhibition of various transcription activities which may get accelerated during cancer development. The aim of proposed study is to develop effective isoform selective Histone deacetylase inhibitor. Synthesis of N-(2-Aminophenyl)-3-Quinolin-4-yl-Prop-2-Enamide derivatives from isatin and its derivatives was achieved. Synthesis was carried out in two steps with good yield. 21 Compounds were synthesized and found to be effective with IC50s in between 3.694 - 38.4µmol in human HCT-116, COLO 205 and COLO 320 DM colon cancer cells in vitro. For the cytotoxicity activity study MTT assay method was adopted. Docking studies were performed initially with HDAC8 enzyme using V-life MDS software for synthesized compounds and had selected best fit molecules for synthesis. The synthesized molecules are effective as colon anticancer agents.

Histone Deacetylase Inhibitors and Antioxidants From the Root of Gluta usitata

A new glycoside, glutacoside (1), as well as 6 known compounds was isolated and identified from the root of Gluta usitata. Their structures were determined by Infrared spectroscopy, Mass spectroscopy, and 1-Dimensional and 2-dimensional nuclear magnetic resonance spectroscopy data. The histone deacetylase (HDAC) inhibitory and antioxidant activities of the obtained compounds were evaluated. Molecular docking experiments of the selected compound with representatives of class I (HDAC2 and HDAC8) and class II (HDAC4 and HDAC7) HDAC isoforms displayed potential isoform-selective HDAC inhibitors. Molecular docking data showed consistent results to the in vitro experiments with the highest potency against HDAC8. The docking studies suggested that the phenolic and carbonyl group can be favorably accommodated at the gorge region of the binding site. Furthermore, the phenolic groups also acted as major roles for antioxidant activities.

Development of classification models for identification of important structural features of isoform-selective histone deacetylase inhibitors (class I).

As one of the hot topics in the epigenetic studies, histone deacetylases inhibitors (HDACIs) have been introduced to treat a variety of diseases such as cancer, immune disorder and neuronal diseases. Given the high numbers of available pathways in which HDACs are involved, the HDACIs that act particularly on Class I or Class II enzymes are considered as possible candidates for anticancer drugs. Due to their effective roles in the onset of cancer and its progression, HDAC Class I isoforms (HDAC 1, 2, 3 and 8) were considered in this study. Herein, our objective is to determine the important isoform-selective and isoform-active structural features of HDACIs using the valid classification models. For this purpose, a diverse dataset comprising 8224 HDAC modulators was collected from the binding database. To identify the significant discriminative features, five classification models were generated by supervised Kohonen network and support vector machine methods. Variable importance in projection method was used as a variable selection approach. The results obtained from descriptor analysis show that physicochemical properties, such as hydrogen bonding, number of branches, size, flexibility, polarity and sphericity in the structure of molecules, were closely related to the bioactivity of HDACIs. The reliability and predictive ability of the conducted models were evaluated using the tenfold cross-validation techniques, test sets and applicability domain analysis. All of the obtained classification models represented high statistical quality and predictive ability with accuracy greater than 85% for the test sets. The proposed strategy and the selective patterns represented in this paper can be applied by researchers in the pharmaceutical sciences who aim to use the same idea for the design of drugs with improved anticancer properties.