Adding a Lysine Mimic in the Design of Potent Inhibitors of Histone Lysine Methyltransferases

JOURNAL OF MOLECULAR BIOLOGY

卷:400

Article

Chang, Yanqi²  Ganesh, Thota¹  Horton, John R.²  Spannhoff, Astrid³  Liu, Jin¹  Sun, Aiming¹  Zhang, Xing²  Bedford, Mark T.³  Shinkai, Yoichi⁴  Snyder, James P.¹  Cheng, Xiaodong² 

[1] Emory Univ, Dept Chem, Atlanta, GA 30322 USA

[2] Emory Univ, Dept Biochem, Atlanta, GA 30322 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78957 USA

[4] Kyoto Univ, Expt Res Ctr Infect Dis, Inst Virus Res, Sakyo Ku, Kyoto 6068507, Japan

关键词: epigenetics;    histone lysine methylation;    enzymatic inhibition;    lysine mimics;   

DOI  :  10.1016/j.jmb.2010.04.048

来源: Elsevier

【 摘 要 】

Dynamic histone lysine methylation involves the activities of modifying enzymes (writers), enzymes removing modifications (erasers), and readers of the histone code. One common feature of these activities is the recognition of lysines in methylated and unmethylated states, whether they are substrates, reaction products, or binding partners. We applied the concept of adding a lysine mimic to an established inhibitor (BIX-01294) of histone H3 lysine 9 methyltransferases G9a and G9a-like protein by including a 5-aminopentyloxy moiety, which is inserted into the target lysine-binding channel and becomes methylated by G9a-like protein, albeit slowly. The compound enhances its potency in vitro and reduces cell toxicity in vivo. We suggest that adding a lysine or methyl-lysine mimic should be considered in the design of small-molecule inhibitors for other methyllysine writers, erasers, and readers. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free