Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification
Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification
复制标题
发现具有抗肿瘤活性的热休克蛋白 90 共价抑制剂，可通过 C 端修饰阻断共伴侣结合
DOI：
10.1016/j.chembiol.2021.03.016
复制
发表时间：
2021-10-21
影响因子：
8.6
通讯作者：
Xu, Xiaoli
中科院分区：
文献类型：
--
作者：
Li, Li;Chen, Nannan;Xu, Xiaoli
热休克蛋白90（Heat shock protein，Hsp 90）是一种重要的分子伴侣，调节大量致癌客户蛋白的成熟，在肿瘤细胞的生长过程中起重要作用。本文中，DDO-6600通过计算机模拟研究被鉴定为Hsp 90上Cys 598的共价修饰，并通过一系列生物测定法进行了验证。我们证明DDO-6600共价结合到Hsp 90 C末端的Cys 598上，并且对多种肿瘤细胞表现出抗增殖活性而不抑制ATP酶活性。进一步的研究表明，DDO-6600破坏了Hsp 90和Cdc 37之间的相互作用，从而诱导多种肿瘤细胞系中激酶客户蛋白的降解，促进细胞凋亡，并抑制细胞运动。我们的研究结果提供了对Hsp 90共价修饰的机械见解，并为开发Hsp 90共价调节剂或化学探针以探索Hsp 90的治疗潜力提供了替代策略。
Heat shock protein (Hsp90), a critical molecular chaperone that regulates the maturation of a large number of oncogenic client proteins, plays an essential role in the growth of neoplastic cells. Herein, DDO-6600 is identified to covalent modification of Cys598 on Hsp90 from in silico study and is verified by a series of biological assays. We demonstrated that DDO-6600 covalently bound to Cys598 on the Hsp90 C terminus and exhibited antiproliferative activities against multiple tumor cells without inhibiting ATPase activity. Further studies showed that DDO-6600 disrupted the interaction between Hsp90 and Cdc37, which induced the degradation of kinase client proteins in multiple tumor cell lines, promoted apoptosis, and inhibited cell motility. Our findings offer mechanic insights into the covalent modification of Hsp90 and provide an alternative strategy for the development of Hsp90 covalent regulators or chemical probes to explore the therapeutical potential of Hsp90.