Optimization and biological evaluation of celastrol derivatives as Hsp90-Cdc37 interaction disruptors with improved druglike properties
Optimization and biological evaluation of celastrol derivatives as Hsp90-Cdc37 interaction disruptors with improved druglike properties
复制标题
雷公藤红醇衍生物作为 Hsp90-Cdc37 相互作用干扰剂的优化和生物学评价，具有改善的药物特性
DOI：
10.1016/j.bmc.2016.08.070
复制
发表时间：
2016-11-01
影响因子：
3.5
通讯作者：
Xu, Xiao-Li
中科院分区：
文献类型：
--
作者：
Jiang, Fen;Wang, Hui-Jie;Xu, Xiao-Li
热休克蛋白90（Hsp 90）作为肿瘤治疗的分子靶点在过去十年中引起了广泛关注。Hsp 90多分子伴侣复合物在癌细胞的生长和/或存活中具有重要作用。Cdc 37作为一种辅助分子伴侣，将激酶客户与Hsp 90联系在一起，促进恶性肿瘤的发展。破坏Hsp 90-Cdc 37相互作用提供了抑制Hsp 90功能用于癌症治疗的替代策略。雷公藤红素作为一种天然产物，可以破坏Hsp 90-Cdc 37相互作用并诱导激酶客户端降解。本研究旨在阐明雷公藤红素衍生物作为Hsp 90-Cdc 37干扰剂的构效关系，并改善其类药性质。设计、合成了23个雷公藤红素衍生物，并测定了其生物活性和理化性质。衍生物CEL 20显示出改善的Hsp 90-Cdc 37破坏活性、抗增殖活性以及药物样性质。此外，CEL 20诱导Panc-1细胞的客户端降解，细胞周期阻滞和凋亡。本研究为发现新型Hsp 90-Cdc 37干扰物提供了参考。(C)2016爱思唯尔有限公司版权所有
Heat shock protein 90 (Hsp90) as a molecular target for oncology therapeutics has attracted much attention in the last decade. The Hsp90 multichaperone complex has important roles in the growth and/or survival of cancer cells. Cdc37, as a cochaperone, associates kinase clients to Hsp90 and promotes the development of malignant tumors. Disrupting the Hsp90-Cdc37 interaction provides an alternative strategy to inhibit the function of Hsp90 for cancer therapy. Celastrol, as a natural product, can disrupt the Hsp90-Cdc37 interaction and induce degradation of kinase clients. The study conducted here attempted to elucidate the structure-activity relationship of celastrol derivatives as Hsp90-Cdc37 disruptors and to improve the druglike properties. 23 celastrol derivatives were designed, synthesized, and the biological activities and physicochemical properties were determined. The derivative CEL20 showed improved Hsp90-Cdc37 disruption activity, anti-proliferative activities as well as druglike properties. Additionally, CEL20 induced clients degradation, cell cycle arrest and apoptosis in Panc-1 cells. This study can provide reference for the discovery of novel Hsp90-Cdc37 disruptors. (C) 2016 Elsevier Ltd. All rights reserved.