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

被引：97

作者：

Chang, Yanqi ^{[2
]}

Ganesh, Thota ^{[1
]}

Horton, John R. ^{[2
]}

Spannhoff, Astrid ^{[3
]}

Liu, Jin ^{[1
]}

Sun, Aiming ^{[1
]}

Zhang, Xing ^{[2
]}

Bedford, Mark T. ^{[3
]}

Shinkai, Yoichi ^{[4
]}

Snyder, James P. ^{[1
]}

Cheng, Xiaodong ^{[2
]}

机构：

[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

来源：

JOURNAL OF MOLECULAR BIOLOGY | 2010年 / 400卷 / 01期

基金：

美国国家卫生研究院;

关键词：

epigenetics; histone lysine methylation; enzymatic inhibition; lysine mimics; ACCURATE DOCKING; DISCOVERY; DC-81; GLIDE; G9A;

D O I：

10.1016/j.jmb.2010.04.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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.

引用

页码：1 / 7

页数：7

共 18 条

[1] A modified synthesis of iodoazidoaryl prazosin [J].