title: Identification of a novel aminotetralin class of HDAC6 and HDAC8 selective inhibitors.
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.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai , 720 Cailun Road, Shanghai, 201203 China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Tang
authors.forename: Jason C
authors.initials: JC
authors.lastname: Wong
authors.forename: Weixing
authors.initials: W
authors.lastname: Zhang
authors.forename: Zhanguo
authors.initials: Z
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.forename: Zhenshan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yiping
authors.initials: Y
authors.lastname: Rong
authors.forename: Shijie
authors.initials: S
authors.lastname: Li
authors.forename: Meifang
authors.initials: M
authors.lastname: Zhang
authors.forename: Lingjie
authors.initials: L
authors.lastname: Yu
authors.forename: Teng
authors.initials: T
authors.lastname: Feng
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
authors.forename: Xihan
authors.initials: X
authors.lastname: Wu
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D013764:Tetrahydronaphthalenes; C433811:HDAC6 protein, human; C409470:HDAC8 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases