2. Academic Validation
  3. Identification of a novel aminotetralin class of HDAC6 and HDAC8 selective inhibitors

Identification of a novel aminotetralin class of HDAC6 and HDAC8 selective inhibitors

  • J Med Chem. 2014 Oct 9;57(19):8026-34. doi: 10.1021/jm5008962.
Guozhi Tang 1,  Jason C Wong,  Weixing Zhang,  Zhanguo Wang,  Nan Zhang,  Zhenghong Peng,  Zhenshan Zhang,  Yiping Rong,  Shijie Li,  Meifang Zhang,  Lingjie Yu,  Teng Feng,  Xiongwen Zhang,  Xihan Wu,  Jim Z Wu,  Li Chen
Affiliations

Affiliation

  • 1 Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai , 720 Cailun Road, Shanghai, 201203 China.
PMID: 25238284 DOI: 10.1021/jm5008962
Abstract

Herein we report the identification of a novel class of HDAC6 and HDAC8 selective inhibitors through a unique chemistry and phenotypic screening strategy. Tetrahydroisoquinoline 12 was identified as a potent HDAC6 and HDAC8 dual inhibitor from a focused library through cellular tubulin acetylation and p21 induction screening assays. Scaffold hopping from 12 led to the discovery of an aminotetralin class of HDAC inhibitors. In particular, the 3-R stereoisomer 32 showed highly potent inhibition against HDAC6 and HDAC8 with IC50 values of 50 and 80 nM, respectively. Treatment of neuroblastoma BE(2)C cells with 32 resulted in elevated levels of acetylated tubulin, TrkA, and neurite outgrowth with only marginal effects on p21 induction and histone H3 acetylation. Consistent with its weak enzymatic inhibition of HDAC1, 32 showed significantly less cytotoxicity than SAHA and moderately inhibited the growth of myeloma NCI-H929 and OPM-2 cells.

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