Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Bioorg Med Chem. 2019 Jul 1;27(13):2813-2821. doi: 10.1016/j.bmc.2019.05.006. Epub 2019 May 7.
Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC of 1.53 μM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.
最近，多种激酶抑制剂被报道与 BRD4 相互作用。这为开发新一代 BRD4 选择性抑制剂提供了一种新的结构框架策略。我们从 PLK1 激酶抑制剂 BI-2536 出发，通过修饰二氢喋呤核心设计了 18 个化合物。化合物 23 对 BRD4 具有很强的抑制活性，IC 为 79nM，对 PLK1 没有抑制活性。进行了细胞增殖抑制测定，对 MV4;11 的抑制活性为 1.53μM。细胞凋亡和 Western blot 表明，化合物 23 通过下调 c-Myc 诱导细胞凋亡。这些新型选择性 BRD4 抑制剂为进一步的药物开发提供了新的先导化合物。
