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Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors.

Abstract：

:The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-ε-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 p38α kinase activity >90,000-fold. A BRD4-D1 cocrystal structure indicates that the 1,2,3-triazole is acting as a N-ε-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.

journal_name

ACS Med Chem Lett

journal_title

ACS medicinal chemistry letters

authors

Carlson AS,Cui H,Divakaran A,Johnson JA,Brunner RM,Pomerantz WCK,Topczewski JJ

doi

10.1021/acsmedchemlett.9b00227

subject

Has Abstract

pub_date

2019-08-02 00:00:00

pages

1296-1301

issue

9

issn

1948-5875

journal_volume

10

pub_type

杂志文章

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