Structure-based design and discovery of potent and selective KDM5 inhibitors

被引：39
作者：
Nie, Zhe [1 ]
Shi, Lihong [1 ]
Lai, Chon [1 ]
O'Connell, Shawn M. [1 ,3 ]
Xu, Jiangchun [1 ]
Stansfield, Ryan K. [1 ,4 ]
Hosfield, David J. [2 ]
Veal, James M. [1 ,4 ]
Stafford, Jeffrey A. [1 ,4 ]
机构：
[1] Celgene Corp, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA
[2] Univ Chicago, Ben May Dept Canc Res, 929 East 57th St, Chicago, IL 60637 USA
[3] Pfizer Inc, Groton, CT 06340 USA
[4] Jecure Therapeut, San Diego, CA USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 09期
关键词：
Epigenetics; Histone lysine demethylase; KDM5; Tri-methylated H3K4; Structure-based design; HISTONE DEMETHYLASES; CANCER; CELLS; MELANOMA; TARGETS;
D O I：
10.1016/j.bmcl.2018.03.083
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1. (C) 2018 Elsevier Ltd. All rights reserved.
引用
收藏
页码：1490 / 1494
页数：5
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