设计合理、合成并生物学评价苯并[d]异噁唑衍生物，用作潜在的前列腺癌治疗药物的优势BET双价抑制剂。
Rational design, synthesis and biological evaluation of benzo[d]isoxazole derivatives as potent BET bivalent inhibitors for potential treatment of prostate cancer.
发表日期：2023 Mar 28
作者：
Junhua Li, Run Zhu, Xiaoxi Zhuang, Cheng Zhang, Hui Shen, Xishan Wu, Maofeng Zhang, Cen Huang, Qiuping Xiang, Linxiang Zhao, Yong Xu, Yan Zhang
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
多聚性是有效结合靶蛋白的一种有吸引力的策略。Bromodomain和额外的末端(BET)家族具有两个串联的Bromodomain(BD1和BD2)，被认为是前列腺癌的潜在新靶点。在这里，我们报道了一类基于我们的单价BET抑制剂7(Y06037)的新颖BET二价抑制剂的合理设计、优化和评价。代表性的二价抑制剂17b有效地抑制了LNCaP的细胞生长，其效能比单价抑制剂7高出32倍。此外，17b在2微米下诱导了LNCaP细胞95.1%的PSA回归。进一步的分子对接研究揭示了17b与两个BET Bromodomain的潜在结合模式。我们的研究表明，17b(Y13021)是治疗前列腺癌的有前途的BET二价抑制剂。版权所有©2023 Elsevier Inc.。保留所有权利。
Multivalency is an attractive strategy for effective binding to target protein. Bromodomain and extra-terminal (BET) family features two tandem bromodomains (BD1, BD2), which are considered to be potential new targets for prostate cancer. Herein, we report the rational design, optimization, and evaluation of a class of novel BET bivalent inhibitors based on our monovalent BET inhibitor 7 (Y06037). The representative bivalent inhibitor 17b effectively inhibited the cell growth of LNCaP, exhibiting 32 folds more potency than monovalent inhibitor 7. Besides, 17b induced 95.1 % PSA regression in LNCaP cell at 2 μM. Docking study was further carried out to reveal the potential binding mode of 17b with two BET bromodomains. Our study demonstrates that 17b (Y13021) is a promising BET bivalent inhibitor for the treatment of prostate cancer.Copyright © 2023 Elsevier Inc. All rights reserved.