Discovery of the First Histone Deacetylase 6/8 Dual Inhibitors

Journal of medicinal chemistry, 2013

Hydroxamic acids were designed, synthesized, and evaluated for their ability to selectively inhibit human histone deacetylase 6 (HDAC6). Several inhibitors, including compound 14 (BRD9757), exhibited excellent potency and selectivity despite the absence of a surface-binding motif. The binding of these highly efficient ligands for HDAC6 is rationalized via structure-activity relationships. These results demonstrate that high selectivity and potent inhibition of HDAC6 can be achieved through careful choice of linker element only.

European Journal of Medicinal Chemistry, 2019

Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed only HDAC3 as an additional low nanomolar activity. Low micromolar antiproliferative activities against two breast cancer and four hematological cancer cell lines was supported by pharmacodynamic studies on a preferred molecule, 25d, supporting the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modelling studies of 25d against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compound potency explaining the observed HDAC3/6 selectivity. A subset of the compounds also exhibited good antimalarial activities particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favourable DMPK profile warranting further investigation of the therapeutic potential of these compounds.

Journal of Medicinal Chemistry, 2013

A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-Nhydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.

Medicinal Chemistry Research

Histone deacetylase inhibitors (HDACIs) have emerged as efficient chemotherapeutic agents. Molecular docking studies of hydroxamtes, biphenyl and benzamide derivatives using Human HDAC8 with pdb id: 1T69 have been carried out in order to find the most active anticancer HDACI. AutoDock 4.0 has been used for docking. The most active lead compound has been identified on the basis of strong interactions and IC50 value from the chosen compounds. Five structural analogues have also been designed from the active lead compound.

Journal of Medicinal Chemistry, 2010

Inhibition of histone deacetylases (HDACs) leads to growth arrest, differentiation, or apoptosis of tumor cell lines, suggesting HDACs as promising targets for cancer therapy. At present, only one HDAC inhibitor (HDACi) is used in therapy: suberoylanilide hydroxamic acid (SAHA). Here, we describe the synthesis and biological evaluation of a new series of compounds derived from SAHA by substituting short alkyl chains at various positions of the phenyl ring. Such modifications induced variable effects ranging from partial loss of activity to increased potency. Through molecular modeling, we describe a possible interaction between HDAC7 proline 809, a residue that is strictly conserved within class 2 enzymes only, and the amide group of HDACi, while nuclear magnetic resonance experiments indicated that dimethyl m-substitution may stabilize the inhibitor in the active site. Our data provide novel information on the structure-activity relationship of HDACi and suggest new ways for developing second generation SAHA-like molecules.

Bioorganic & Medicinal Chemistry Letters, 2009

In an effort to identify HDAC isoform selective inhibitors, we designed and synthesized novel, chiral 3,4dihydroquinoxalin-2(1H)-one and piperazine-2,5-dione aryl hydroxamates showing selectivity (up to 40fold) for human HDAC6 over other class I/IIa HDACs. The observed selectivity and potency (IC 50 values 10-200 nM against HDAC6) is markedly dependent on the absolute configuration of the chiral moiety, and suggests new possibilities for use of chiral compounds in selective HDAC isoform inhibition.

Bioorganic & Medicinal Chemistry Letters, 2008

We report herein the initial exploration of novel selective HDAC1/HDAC2 inhibitors (SHI-1:2). Optimized SHI-1:2 structures exhibit enhanced intrinsic activity against HDAC1 and HDAC2, and are greater than 100-fold selective versus other HDACs, including HDAC3. Based on the SAR of these agents and our current understanding of the HDAC active site, we postulate that the SHI-1:2 extend the existing HDAC inhibitor pharmacophore to include an internal binding domain.

Histone deacetylases (HDACs) are enzymes that act on histone proteins to remove the acetyl group and thereby regulate the chromatin state. HDACs act not only on histone protein but also nonhistone proteins that are key players in cellular processes such as the cell cycle, signal transduction, apoptosis, and more. “Classical” HDACs have been shown to be promising targets for anticancer drug design and development. However, the selectivity of HDAC inhibitors for HDAC isoforms remains the motivation of current research in this field. Here, we explored Class I HDACs and HDAC6 by sequence alignment and structural superimposition, catalytic channel extraction, and identification of critical residues involved in HDAC catalysis. Based on the general pharmacophore features of known HDAC inhibitors, we developed a library of compounds by scaffold hopping on a fragment hit identified via structurebased virtual screening of the molecular fragment library retrieved from the Otava database. Molecular docking assay revealed five of these compounds to have increased potency and selectivity for HDACs 1 and 2. Furthermore, their predicted absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties were consistent with those of drug-like compounds. With further modelingbased and experimental investigations, we believe that these findings may offer additional potential HDAC inhibitors with improved selectivity.

Review article, 2019

The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. Discoveries related to the HDAC8 enzyme activity signified the importance of HDAC8 isoform in cell proliferation, tumorigenesis, cancer, neuronal disorders, parasitic/viral infections and other epigenetic regulations. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiological and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiological conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymatic activity.

2017

Background: HDAC inhibition is known to modulate expression of tumour suppressor genes and induce cell differentiation, growth arrest and apoptosis. The aim of this study was to evaluate the efficacy of a novel series of hydroxamic acid based HDAC inhibitors in cell based assays and tumour xenograft models. Material and Methods: A series of novel hydroxamate derivatives were synthesized and evaluated. HDAC enzyme inhibitory activity was measured using Hela nuclear extracts. Anti-proliferative activity was assessed in a panel of cancer cell lines. Anti-apoptotic activity was evaluated by caspase-3 activation. In vivo efficacy was evaluated in lung adenocarcinoma xenograft model. Results: The compounds showed potent HDAC inhibitory activity and anti-proliferative activity in several cancer cell lines. In an in vivo A549 lung xenograft model, the compounds exhibited significant tumor growth inhibition. Conclusion: The novel HDAC inhibitors showed anti-proliferative activity against sev...