Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach

Hsu, Kai Cheng; Liu, Chang Yi; Lin, Tony Eight; Hsieh, Jui Hua; Sung, Tzu Ying; Tseng, Hui-Ju; Yang, Jinn-Moon; Huang, Wei

doi:10.1038/s41598-017-03417-1

Cited by 45 publications

(40 citation statements)

References 75 publications

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“…Conversely, both compounds were inactive against HDAC 4 (representative of Class IIa HDACs) ( Table 4 ). This result was not unexpected, as it is well known that SAHA inhibits class IIa enzymes at concentrations that are not clinically significant [ 41 ].…”

Section: Resultsmentioning

confidence: 62%

Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

Cincinelli

Musso

Artali³

et al. 2018

PLoS ONE

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Recent studies have shown that HDAC inhibitors act synergistically with camptothecin derivatives in combination therapies. To exploit this synergy, new hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.

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Section: Resultsmentioning

confidence: 62%

Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

Cincinelli

Musso

Artali³

et al. 2018

PLoS ONE

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“…Moreover, class II HDACs can be further divided into class IIa and class IIb HDACs. Class IIa HDACs (4, 5, 7, and 9) carry the ability to shuttle between the nucleus and the cytoplasm and are expressed in the brain, heart, and muscle [28]. Class IIb HDACs (6 and 10) are primarily located in the cytoplasm [28], although HDAC6 has also been reported to localize to the sarcomere [7].…”

Section: Histone Deacetylases (Hdacs)mentioning

confidence: 99%

The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

Habibian

Ferguson

2018

IJMS

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Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

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“…Besides, deacetylation of non-histone proteins makes HDACs as popular therapeutic targets to modify different biological processes. Therefore, several molecules have been identified or developed as selective/non-selective inhibitors of HDACs [25][26][27][28][29]. Depending on chemical structures, these inhibitors interact with HDACs differently, which affects their potencies, toxicities and eventually efficacies.…”

Section: Discussionmentioning

confidence: 99%

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

Bora¹,

Sarı²,

Taşkor³

et al. 2019

jrp

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Histone deacetylases (HDAC) are evolutionary conserved enzymes, which catalyze removal of acetyl groups from histone and non-histone proteins, therefore, control multiple biological processes. Inhibition of their activities have been investigated to modify gene expression and/or protein functions not only for treatment of certain diseases but also for understanding functions of deacetylase isoforms. We previously synthesized aryl butenoic acid derivatives and identified their pan-HDAC inhibition activities. In this study, we investigated selective inhibition activities of these derivatives (C1, C3, C4) on class I HDACs using in silico and in vitro approaches. Molecular docking studies of the three aryl butenoic acid derivatives were performed on the crystal structures of HDAC 1, 2, 3 and 8, which were obtained from RCSB protein databank, using Glide software. In vitro inhibition activities of the compounds at two different concentrations were tested using fluorometric assay. In silico results indicated that all the compounds showed higher affinity to HDAC 1 and 8 than other class I deacetylases. In vitro analysis showed that the compounds inhibit HDAC 8 more effectively than HDAC 1. It was shown that C1 had higher binding affinity and inhibition activity to both enzymes. We concluded that, C1 inhibited both HDAC 1 and 8, however, C3 and C4 showed slight selectivity for HDAC 8 over HDAC 1, which was in agreement with the docking studies. Further cell culture studies will be valuable to determine increased acetylation on target proteins in response to compound treatment.

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Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach

Cited by 45 publications

References 75 publications

Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

Class I histone deacetylase inhibition by aryl butenoic acid derivatives: In silico and in vitro studies

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