jm9b01290_si_001.pdf (4.4 MB)
Discovery of Novel Celastrol Derivatives as Hsp90–Cdc37 Interaction Disruptors with Antitumor Activity
journal contribution
posted on 2019-12-02, 23:13 authored by Na Li, Manyi Xu, Bing Wang, Zhixian Shi, Zihao Zhao, Yunqing Tang, Xinyue Wang, Jianbo Sun, Li ChenTo develop novel
and efficient
heat shock protein 90–cell division cycle 37 (Hsp90–Cdc37)
interaction disruptors, several lipophilic fragments were introduced
into celastrol (CEL) to synthesize 48 new CEL derivatives. Among all
the target compounds, 41 was screened with superior antiproliferative
activity on related cancer cells (IC50: 0.41–0.94
μM) and 41 could decrease the level of the Hsp90–Cdc37
complex in A549 cells. The capability to disrupt the Hsp90–Cdc37
interaction was stronger than that of CEL. Furthermore, pull-down
assay, UV assay, and molecular docking analysis all showed that 41 might disrupt the interaction of the Hsp90–Cdc37
complex by preferentially binding to Cdc37 in cancer cells. Further
studies showed that 41 could significantly regulate the
levels of Hsp90–Cdc37 clients, thereby inducing the apoptosis
of cancer cells. Together, 41 is a novel Hsp90–Cdc37
disruptor by binding to Cdc37 (hydrogen bond and/or covalent bond).
Our results may provide reference for the discovery of effective Hsp90–Cdc37
disruptors.