Structure-Based Discovery and Optimization of Benzo[&ITd&IT]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)
Structure-Based Discovery and Optimization of Benzo[&ITd&IT]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC)
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基于结构的苯并的发现和优化[
DOI：
10.1021/acs.jmedchem.8b00103
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发表时间：
2018
影响因子：
7.3
通讯作者：
Xu Yong
中科院分区：
文献类型：
--
作者：
Zhang Maofeng;Zhang Yan;Song Ming;Xue Xiaoqian;Wang Junjian;Wang Chao;Zhang Cheng;Li Chenchang;Xiang Qiuping;Zou Lingjiao;Wu Xishan;Wu Chun;Dong Baijun;Xue Wei;Zhou Yulai;Chen Hongwu;Wu Donghai;Ding Ke;Xu Yong
布罗莫结构域和额外末端（BET）家族蛋白作为治疗去势抵抗性前列腺癌（CRPC）的药物靶标已经获得越来越多的关注。在这里，我们描述了作为有效的BET溴结构域抑制剂的含苯并[d]异恶唑的化合物的设计、优化和评价。典型抑制剂与BRD 4（1）配合物的共晶结构为化合物的优化提供了坚实的结构基础。两种最有效的化合物6 i（Y 06036）和7 m（Y 06137）分别以82和81 nM的Kd值结合BRD 4（1）溴结构域。它们还表现出对其他非BET亚家族成员的高选择性。这些化合物有效抑制前列腺癌细胞系中的细胞生长、集落形成以及AR、AR调节基因和MYC的表达。化合物6 i和7 m还在小鼠的C4-2B CRPC异种移植肿瘤模型中显示出治疗效果。这些有效的和选择性的BET抑制剂代表了一类新的化合物，用于开发针对CRPC的潜在治疗剂。
The bromodomain and extra-terminal (BET) family proteins have gained increasing interest as drug targets for treatment of castration-resistant prostate cancer (CRPC). Here, we describe the design, optimization, and evaluation of benzo[d]isoxazole-containing compounds as potent BET bromodomain inhibitors. Cocrystal structures of the representative inhibitors in complex with BRD4(1) provided solid structural basis for compound optimization. The two most potent compounds,6i(Y06036) and7m(Y06137), bound to the BRD4(1) bromodomain withKdvalues of 82 and 81 nM, respectively. They also exhibited high selectivity over other non-BET subfamily members. The compounds potently inhibited cell growth, colony formation, and the expression of AR, AR regulated genes, and MYC in prostate cancer cell lines. Compounds6iand7malso demonstrated therapeutic effects in a C4-2B CRPC xenograft tumor model in mice. These potent and selective BET inhibitors represent a new class of compounds for the development of potential therapeutics against CRPC.