Inhibition of Zinc-Dependent Histone Deacetylases with a Chemically Triggered Electrophile

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• 作者：Zarko V. Boskovic ; Melissa M. Kemp ; Allyson M. Freedy ; Vasanthi S. Viswanathan ; Marius S. Pop ; Jason H. Fuller ; Nicole M. Martinez ; Samuel O. Figueroa Lazú ; Jiyoung A. Hong ; Timothy A. Lewis ; Daniel Calarese ; James D. Love ; Amedeo Vetere ; Steven C. Almo ; Stuart L. Schreiber ; Angela N. Koehler
• 刊名：ACS Chemical Biology
• 出版年：2016
• 出版时间：July 15, 2016
• 年：2016
• 卷：11
• 期：7
• 页码：1844-1851
• 全文大小：551K
• 年卷期：0
• ISSN：1554-8937

文摘

Unbiased binding assays involving small-molecule microarrays were used to identify compounds that display unique patterns of selectivity among members of the zinc-dependent histone deacetylase family of enzymes. A novel, hydroxyquinoline-containing compound, BRD4354, was shown to preferentially inhibit activity of HDAC5 and HDAC9 in vitro. Inhibition of deacetylase activity appears to be time-dependent and reversible. Mechanistic studies suggest that the compound undergoes zinc-catalyzed decomposition to an ortho-quinone methide, which covalently modifies nucleophilic cysteines within the proteins. The covalent nature of the compound–enzyme interaction has been demonstrated in experiments with biotinylated probe compound and with electrospray ionization–mass spectrometry.