BRD4小分子抑制剂的设计、合成以及初步活性研究

Design, synthesis and evaluation of a novel BRD4 protein inhibitors

含溴结构域的蛋白(bromodomain-containing proteins,BCPs)可以特异性识别组蛋白的乙酰化赖氨酸(KAc)。近年来的研究表明一些激酶抑制剂也可以结合于溴结构域,如PLK1抑制剂BI-2536和JAK2抑制剂TG101209。为了获得新颖结构类型的溴结构域BRD4抑制剂,本研究基于抑制剂BI-2536的结合特点,采用二氢喹喔啉-2(1H)-酮代替BI-2536中的7,8-二氢蝶啶-6(5H)-酮。通过探索新的二氢喹喔啉-2(1H)-酮骨架的构效关系,最终获得一类结构新颖的具有苯基侧链的BRD4抑制剂。在该系列化合物中,获得的一些活性较好的BRD4抑制剂如化合物16、22、28和29,它们在荧光各向异性方法 (fluorescence anisotropy,FA)的分子结合测试中IC50均小于100 nmol·L^(-1),值得进一步深入研究。

Bromodomain-containing proteins（BCPs） can specifically recognize acetylated lysine（KAc） in histones and other substrate proteins. Recently, several kinase inhibitors were found to inhibit bromodomains, such as the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which bind to BRD4 with IC50 values of 25 nmol·L^-1 and 130 nmol·L^-1, respectively. To obtain potent BRD4 inhibitors from inhibitor BI-2536, we used dihydroquinoxalin-2（1H）-one to replace the 7,8-dihydropteridin-6（5H）-one in BI2536. By exploring the structure-activity relationships of the new dihydroquinoxalin-2（1H）-one structures, we obtained a novel phenyl side chain series of BRD4 inhibitors. We identified several potent BRD4 inhibitors, especially compounds 16, 22, 28 and 29, which had IC50 values below 100 nmol·L^-1 in fluorescence anisotropy（FA） assays, indicating this series of compounds are worth to fruther investigation.