2. Academic Validation
  3. Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors

Design and synthesis of orally bioavailable aminopyrrolidinone histone deacetylase 6 inhibitors

  • J Med Chem. 2015 Mar 26;58(6):2809-20. doi: 10.1021/jm502011f.
Xianfeng Lin 1,  Wenming Chen 1,  Zongxing Qiu 1,  Lei Guo 1,  Wei Zhu 1,  Wentao Li 1,  Zhanguo Wang 1,  Weixing Zhang 1,  Zhenshan Zhang 1,  Yiping Rong 1,  Meifang Zhang 1,  Lingjie Yu 1,  Sheng Zhong 1,  Rong Zhao 1,  Xihan Wu 1,  Jason C Wong 1,  Guozhi Tang 1
Affiliations

Affiliation

  • 1 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, 720 Cailun Road, Shanghai 201203, China.
PMID: 25734520 DOI: 10.1021/jm502011f
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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