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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lin X,Chen W,Qiu Z,Guo L,Zhu W,Li W,Wang Z,Zhang W,Zhang Z,Rong Y,Zhang M,Yu L,Zhong S,Zhao R,Wu X,Wong JC,Tang Gdoi
10.1021/jm502011fsubject
Has Abstractpub_date
2015-03-26 00:00:00pages
2809-20issue
6eissn
0022-2623issn
1520-4804journal_volume
58pub_type
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