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      Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction

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          Abstract

          A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.

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          Most cited references31

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          The many roles of histone deacetylases in development and physiology: implications for disease and therapy.

          Histone deacetylases (HDACs) are part of a vast family of enzymes that have crucial roles in numerous biological processes, largely through their repressive influence on transcription. The expression of many HDAC isoforms in eukaryotic cells raises questions about their possible specificity or redundancy, and whether they control global or specific programmes of gene expression. Recent analyses of HDAC knockout mice have revealed highly specific functions of individual HDACs in development and disease. Mutant mice lacking individual HDACs are a powerful tool for defining the functions of HDACs in vivo and the molecular targets of HDAC inhibitors in disease.
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            Histone deacetylase 6 structure and molecular basis of catalysis and inhibition

            Histone deacetylase 6 (HDAC6) is a critical target for drug design due to its role in oncogenic transformation and cancer metastasis, and is unique among all histone deacetylases in that it contains tandem catalytic domains designated CD1 and CD2. We now report the crystal structures of CD2 from Homo sapiens and CD1 and CD2 from Danio rerio HDAC6, and we correlate these structures with activity measurements using a panel of 13 different substrates. The catalytic activity of CD2 from both species exhibits broad substrate specificity, whereas that of CD1 is highly specific for substrates bearing C-terminal acetyllysine residues. Crystal structures of substrate complexes yield unprecedented snapshots of the catalytic mechanism. Additionally, crystal structures of complexes with 8 different inhibitors, including Belinostat and Panobinostat (currently used in cancer chemotherapy), the macrocyclic tetrapeptide HC toxin, and the HDAC6-specific inhibitor N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide, reveal surprising new insight regarding changes in Zn2+ coordination and isozyme-specific inhibition.
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              Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease

              Lysine acetylation is a conserved, reversible, post-translational protein modification regulated by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs; also known as histone deacetylases (HDACs)) that is involved in many cellular signalling pathways and diseases. Studies in animal models have revealed a regulatory role of reversible lysine acetylation in hypertension, vascular diseases, arrhythmia, heart failure and angiogenesis. Evidence from these studies indicates a therapeutic role of KDAC inhibitors (also known as HDAC inhibitors) in cardiovascular diseases. In this Review, we describe the diverse roles of KATs and KDACs in both the normal and the diseased heart. Among KDACs, class II and class III HDACs seem to have a protective role against both cardiac damage and vessel injury, whereas class I HDACs protect against vessel injury but have deleterious effects on the heart. These observations have important implications for the clinical utility of HDAC inhibitors as therapeutic agents for cardiovascular diseases. In addition, we summarize the latest data on nonacetylation acylations in the context of cardiovascular disease.
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                Author and article information

                Journal
                ACS Med Chem Lett
                ACS Med Chem Lett
                ml
                amclct
                ACS Medicinal Chemistry Letters
                American Chemical Society
                1948-5875
                07 March 2021
                08 April 2021
                07 March 2021
                : 12
                : 4
                : 540-547
                Affiliations
                MRL, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States
                Author notes
                Article
                10.1021/acsmedchemlett.1c00074
                8040053
                f476c4f6-82f2-4589-b17d-16048e799f77
                © 2021 American Chemical Society

                Made available for a limited time for personal research and study only License.

                History
                : 31 January 2021
                : 24 February 2021
                Categories
                Featured Letter
                Custom metadata
                ml1c00074
                ml1c00074

                Pharmaceutical chemistry
                hdac inhibitor,zinc binding,pharmacophore,hiv latency
                Pharmaceutical chemistry
                hdac inhibitor, zinc binding, pharmacophore, hiv latency

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