Ayoub Alex M, Hawk Laura M L, Herzig Ryan J, Jiang Jiewei, Wisniewski Andrea J, Gee Clifford T, Zhao Peiliang, Zhu Jin-Yi, Berndt Norbert, Offei-Addo Nana K, Scott Thomas G, Qi Jun, Bradner James E, Ward Timothy R, Schönbrunn Ernst, Georg Gunda I, Pomerantz William C K
Department of Chemistry, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States.
Department of Medicinal Chemistry and Institute for Therapeutics Discovery and Development, University of Minnesota , 717 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
J Med Chem. 2017 Jun 22;60(12):4805-4817. doi: 10.1021/acs.jmedchem.6b01336. Epub 2017 Jun 7.
Chemical inhibition of epigenetic regulatory proteins BrdT and Brd4 is emerging as a promising therapeutic strategy in contraception, cancer, and heart disease. We report an easily synthesized dihydropyridopyrimidine pan-BET inhibitor scaffold, which was uncovered via a virtual screen followed by testing in a fluorescence anisotropy assay. Dihydropyridopyimidine 3 was subjected to further characterization and is highly selective for the BET family of bromodomains. Structure-activity relationship data and ligand deconstruction highlight the importance of the substitution of the uracil moiety for potency and selectivity. Compound 3 was also cocrystallized with Brd4 for determining the ligand binding pose and rationalizing subsequent structure-activity data. An additional series of dihydropyridopyrimidines was synthesized to exploit the proximity of a channel near the ZA loop of Brd4, leading to compounds with submicromolar affinity and cellular target engagement. Given these findings, novel and easily synthesized inhibitors are being introduced to the growing field of bromodomain inhibitor development.
对表观遗传调节蛋白BrdT和Brd4进行化学抑制，正成为避孕、癌症和心脏病治疗中一种有前景的治疗策略。我们报告了一种易于合成的二氢吡啶嘧啶泛BET抑制剂支架，它是通过虚拟筛选发现的，随后在荧光偏振分析中进行了测试。二氢吡啶嘧啶3经过进一步表征，对BET家族的溴结构域具有高度选择性。构效关系数据和配体解构突出了尿嘧啶部分取代对效力和选择性的重要性。化合物3还与Brd4共结晶，以确定配体结合构象并合理化后续的构效数据。合成了另一系列二氢吡啶嘧啶，以利用Brd4的ZA环附近通道的接近性，从而得到具有亚微摩尔亲和力和细胞靶点结合能力的化合物。基于这些发现，新型且易于合成的抑制剂正被引入到不断发展的溴结构域抑制剂开发领域。
