Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, United States.
Department of Molecular Medicine, USF Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
J Med Chem. 2021 Nov 11;64(21):15772-15786. doi: 10.1021/acs.jmedchem.1c01096. Epub 2021 Oct 28.
BRD4 and other members of the bromodomain and extraterminal (BET) family of proteins are promising epigenetic targets for the development of novel therapeutics. Among the reported BRD4 inhibitors are dihydropteridinones and benzopyrimidodiazepinones originally designed to target the kinases PLK1, ERK5, and LRRK2. While these kinase inhibitors were identified as BRD4 inhibitors, little is known about their binding potential and structural details of interaction with the other BET bromodomains. We comprehensively characterized a series of known and newly identified dual BRD4-kinase inhibitors against all eight individual BET bromodomains. A detailed analysis of 23 novel cocrystal structures of BET-kinase inhibitor complexes in combination with direct binding assays and cell signaling studies revealed significant differences in molecular shape complementarity and inhibitory potential. Collectively, the data offer new insights into the action of kinase inhibitors across BET bromodomains, which may aid the development of drugs to inhibit certain BET proteins and kinases differentially.
BRD4 和其他溴结构域和末端外结构域（BET）家族的蛋白是新兴的表观遗传靶点，可用于开发新型治疗药物。已报道的 BRD4 抑制剂包括最初设计用于靶向激酶 PLK1、ERK5 和 LRRK2 的二氢蝶啶酮和苯并嘧啶二氮杂卓。虽然这些激酶抑制剂被鉴定为 BRD4 抑制剂，但它们与其他 BET 溴结构域的结合潜力和结构细节知之甚少。我们全面表征了一系列已知和新鉴定的双重 BRD4-激酶抑制剂对所有八个单独的 BET 溴结构域。对 23 个新的 BET-激酶抑制剂复合物的共晶结构的详细分析，结合直接结合测定和细胞信号研究，揭示了分子形状互补性和抑制潜力的显著差异。总的来说，这些数据提供了对激酶抑制剂在 BET 溴结构域中作用的新见解，这可能有助于开发抑制某些 BET 蛋白和激酶的药物。
