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.
Bibliographical noteFunding Information:
We acknowledge Daniel A. Harki for his helpful discussions during this project. MM.1S cells were a gift from Dr. Brian Van Ness at the University of Minnesota. This work was supported by the NIGMS (Grant R35GM124718), the American Cancer Society (# 129819-IRG-16-189-58-IRG88), the University of Minnesota Masonic Cancer Center (Pre-R01 pilot grant), and the University of Minnesota. J.J. was supported by a National Institutes of Health Biotechnology training grant 5T32GM008347-23. A.D. was supported by the NIH chemistry–biology interface training grant at the University of Minnesota, 5T32GM008700-18.