Discovery of Novel Celastrol Derivatives as Hsp90–Cdc37 Interaction Disruptors with Antitumor Activity

Abstract

To 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, <b>41</b> was screened with superior antiproliferative activity on related cancer cells (IC₅₀: 0.41-0.94 μM) and <b>41</b> 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 <b>41</b> might disrupt the interaction of the Hsp90-Cdc37 complex by preferentially binding to Cdc37 in cancer cells. Further studies showed that <b>41</b> could significantly regulate the levels of Hsp90-Cdc37 clients, thereby inducing the apoptosis of cancer cells. Together, <b>41</b> 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.