Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors

Journal of Medicinal Chemistry
Xianfeng LinGuozhi Tang

Abstract

Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic agents. Herein we report the design, synthesis, and phenotypic screening of a novel class of 3-aminopyrrolidinone-based hydroxamic acids as HDAC6 inhibitors. In particular, the α-methyl-substituted enantiomer 33 (3-S) showed significant in-cell tubulin acetylation (Tub-Ac) with an EC50 of 0.30 μM but limited impact on p21 levels at various concentrations. In enzyme inhibition assays, 33 demonstrated high selectivity for HDAC6 with an IC50 of 0.017 μM and selectivity indexes of 10 against HDAC8 and over 4000 against HDAC1-3 isoforms. Moreover, 33 has suitable drug metabolism and pharmacokinetics properties compared with other hydroxamic acid-based HDAC inhibitors, warranting further biological studies and development as a selective HDAC6 inhibitor.

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Citations

Jun 19, 2016·European Journal of Medicinal Chemistry·Joëlle Roche, Philippe Bertrand
Nov 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Teru HideshimaJames E Bradner
Dec 31, 2016·Expert Opinion on Therapeutic Patents·Hai-Tao QinFeng Liu
Feb 6, 2020·Cancers·Hélène LossonMarc Diederich
Mar 7, 2020·Journal of Zhejiang University. Science. B·Er-Rong DuChang-Shui Xu
Dec 31, 2018·European Journal of Medicinal Chemistry·Suvankar BanerjeeTarun Jha
Nov 11, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Sravani PulyaBalaram Ghosh
Jan 12, 2021·ChemMedChem·Jelena MelesinaWolfgang Sippl
Jul 22, 2018·Journal of Medicinal Chemistry·Hsueh-Yun LeeJing-Ping Liou

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