The structural requirements of histone deacetylase inhibitors: SAHA analogs modified at the C5 position display dual HDAC6/8 selectivity

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Negmeldin, Ahmed T.¹  Pflum, Mary Kay H.¹ 

[1] Wayne State Univ, Dept Chem, 5101 Cass Ave, Detroit, MI 48202 USA

关键词: Histone deacetylase;    HDAC inhibitors;    Vorinostat;    Isoform selectivity;    HDAC6/8 selective inhibitor;   

DOI  :  10.1016/j.bmcl.2017.06.033

来源: Elsevier

【 摘 要 】

Histone deacetylase (HDAC) proteins have emerged as important targets for anti-cancer drugs, with four small molecules approved for use in the clinic. Suberoylanilide hydroxamic acid (Vorinostat, SAHA) was the first FDA-approved HDAC inhibitor for cancer treatment. However, SAHA inhibits most of the eleven HDAC isoforms. To understand the structural requirements of HDAC inhibitor selectivity and develop isoform selective HDAC inhibitors, SAHA analogs modified in the linker at the C5 position were synthesized and tested for potency and selectivity. C5-modified SAHA analogs displayed dual selectivity to HDAC6 and HDAC8 over HDAC 1, 2, and 3, with only a modest reduction in potency. These findings are consistent with prior work showing that modification of the linker region of SAHA can alter isoform selectivity. The observed HDAC6/8 selectivity of C5-modified SAHA analogs provide guidance toward development of isoform selective HDAC inhibitors and more effective anti-cancer drugs. (C) 2017 Elsevier Ltd. All rights reserved.

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