期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 10, 期 9, 页码 1296-+出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00227
关键词
Bromodomains; BET; BRD4; p38 alpha; kinases
资金
- NIGMS [R35GM124718]
- American Cancer Society [129819-IRG-16-189-58-IRG88]
- University of Minnesota Masonic Cancer Center (Pre-R01 pilot grant)
- University of Minnesota
- National Institutes of Health Biotechnology training grant [5T32GM008347-23]
- NIH chemistry-biology interface training grant at the University of Minnesota [5T32GM008700-18]
The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-epsilon-acetylated lysine modifications, regulating transcription as reader proteins. Bromodomain inhibitors are interesting targets for the development of potential cancer, inflammation, and heart disease treatments. Several dual kinase-bromodomain inhibitors have been identified by screening kinase inhibitor libraries against BET proteins. Although potentially useful from a polypharmacology standpoint, multitarget binding complicates deciphering molecular mechanisms. This report describes a systematic approach to mitigating kinase activity in a dual kinase-bromodomain inhibitor based on a 1,2,3-triazole-pyrimidine core. By modifying the triazole substituent and altering the pyrimidine core, this structure-activity relationship study enhanced BET activity while reducing the p38 alpha kinase activity >90,000-fold. A BRD4-D1 cocrystal structure indicates that the 1,2,3-triazole is acting as a N-epsilon-acetylated lysine mimic. A BRD4 sensitive cell line, MM.1S, was used to demonstrate activity in cells, which is further supported by reduced c-Myc expression.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据