基于ZAc热点区域的BRD4 Bromodomain抑制剂设计与活性研究  

Design and evaluation of potent BRD4 Bromodomain inhibitors based on ZA channel hot spot

作　　者：李慧丽 李珏 何丹丹 陶玲[1] 江渝斌 沈祥春[1,2] 姜飞 Huili Li;Jue Li;Dandan He;Ling Tao;Yubing Jiang;Xianghun Shen;Fei Jiang(State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University,Guiyang 550025,Guizhou,China;The Key Laboratory of Optimal Utilization of Natural Medicine Resources,Guizhou Medical University,Guiyang 550025,Guizhou,China)

机构地区：[1]贵州医科大学省部共建药用植物功效与利用国家重点实验室,贵州贵阳550025 [2]贵州医科大学药学院天然药物资源优效利用重点实验室,贵州贵阳550025

出　　处：《Journal of Chinese Pharmaceutical Sciences》2023年第12期971-988,共18页中国药学（英文版）

基　　金：Guizhou Province Ordinary Colleges and Universities Youth Science and Technology Talent Growth Project (Grant No. QJH-KY[2022]249, QJH-KY[2022]250);Science and Technology Fund of Guizhou Provincial Health Commission (Grant No. GZWKJ2022-464 and GZWKJ2022-466);the Basic Research Program of Guizhou Province,Guizhou Provience Science and Technology Foundation,China (Grant No. QKHJC-ZK[2021]YB553, QKHRCZK[2023]YB308, and QKHJC-ZK[2023]ZD035);Cultivation Project of National Natural Science Foundation of Guizhou Medical University (Grant No. 20NSP052);The Start-up Foundation for Doctors of Guizhou Medical University (Grant No. YJ2020-BK035);Provincial College Student Innovation,Entrepreneurship Training Program (Grant No. S202010660142);the Guizhou Provincial Scientific and Technologic Innovation Base (Grant No.[2023]003);the National Natural Science Foundation of China (Grant No. 22307026)。

摘　　要：Bromodomain是一种表观遗传读取器,在识别乙酰化组蛋白方面发挥关键功能而越来越受到关注。Bromodomain结构域的蛋白质与多种疾病的发展有关,靶向Bromodomain结构域已成为开发蛋白质-蛋白质相互作用抑制剂的重要策略。本研究在BRD4的乙酰赖氨酸结合位点中发现了ZA通道上的新热点。为探究该热点的重要性,对基于结构的3,5-二甲基异恶唑基BRD4抑制剂(4)进行了药物设计,并围绕ZA通道热点合成了一系列具有结构修饰的衍生物。结构优化产生了具有纳摩尔蛋白和细胞效力的有前途的衍生物21。研究表明,ZA通道热点可能在BRD4抑制剂的活性和选择性中起重要作用。Bromodomain, an epigenetic reader module, is garnering increasing interest due to its critical function in recognizing acetylated histones. Bromodomain-containing proteins have been implicated in the development of various diseases, making the targeting of bromodomain a significant strategy for developing protein-protein interaction(PPI) inhibitors. In the present study, a novel hot spot was identified on the ZA channel, which is located in the acetyl lysine binding site of BRD4. To investigate the significance of this hot spot, structure-based drug design was conducted on a 3,5-dimethylisoxazole-based BRD4 inhibitor(4). A series of derivatives were synthesized with structural modifications focusing on the ZA channel hot spot. Through structural optimization, a promising derivative compound 21, was developed, demonstrating nanomolar protein and cell potency. This study suggested that the ZA channel hot spot might play a crucial role in the activity and selectivity of BRD4 inhibitors.

关 键 词：蛋白-蛋白相互作用 BRD4 ZAc区域 急性髓性白血病细胞 

分 类 号：R916[医药卫生—药学]