Members of the bromodomain and extra terminal (BET) family of proteins are essential for the recognition of acetylated lysine (KAc) residues in histones and have emerged as promising drug targets in cancer, inflammation and contraception research. In co-crystallization screening campaigns using the first bromodomain of BRD4 against kinase inhibitor libraries, we identified and characterized 14 kinase inhibitors (10 distinct chemical scaffolds) as ligands of the KAc binding site. Among these, the PLK-1 inhibitor BI2536 and the JAK2-FLT3 inhibitors TG101209 and TG101348 displayed strongest inhibitory potential against BRD4 (IC50 values of 25 nM and 130 nM, respectively) and high selectivity for BET bromodomains. Comparative structural analysis revealed markedly different binding modes of kinase hinge-binding scaffolds in the KAc binding site. The results suggest that BET proteins are potential off-targets of diverse kinase inhibitors, the knowledge of which could significantly impact kinase drug development campaigns. BI2536 and TG101348 inhibit the intended kinase targets and BET proteins simultaneously and effectively at relatively low concentrations. Knapp and colleagues recently demonstrated that both inhibitors potently suppressed c-Myc expression (a cellular marker of BET inhibition) in multiple myeloma cells, and TG101348 potently inhibited proliferation of AML cells driven by BET bromodomains and mutant FLT3. Combined, these findings provide a new structural framework for the rational design of next-generation BET-selective and dual kinase-BET inhibitors able to target multiple disease pathways with improved efficacy over traditional combination therapies

BET bromodomains interact with diverse kinase inhibitors

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.