28373-77-5Relevant academic research and scientific papers
Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors
Carlson, Angela S.,Cui, Huarui,Divakaran, Anand,Johnson, Jorden A.,Brunner, Ryan M.,Pomerantz, William C. K.,Topczewski, Joseph J.
, p. 1296 - 1301 (2019)
The Bromodomain and Extra Terminal (BET) family of proteins recognize post-translational N-?-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-?-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.
THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
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Paragraph 0140; 0141, (2020/12/13)
The invention provides a compound of formula I: or a salt thereof, wherein R1, R2, R3, A, B, D, E, F and G have any of the values described in the specification, as well as compositions comprising a compound of formula I.
