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, 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.

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Contributions: (I) Conception and design: Z Song, J Wei; (II) Administrative support: Z Song; (III) Provision of study materials and patients: Z Song;

To discover celastrol (CEL) derivatives with enhanced Hsp90–Cdc37 inhibition, C-20-COOH was introduced with various substituted imidazoles, which might affect the Michael addition of CEL by nucleophilic attack. The most potent compound 9, which showed higher antiproliferation, covalent-binding ability, and Hsp90–Cdc37 inhibition than CEL, was selected from 28 new target compounds. Then, the binding sites and the docking mode of 9 to Hsp90 and Cdc37 were studied. Furthermore, the activity of 9 sharply decreased or even disappeared in the Hsp90- and/or Cdc37-overexpressing A549 cells, indicating that the activity was related to its combination with Hsp90 and Cdc37. Moreover, 9 could more effectively induce apoptosis and inhibit tumor growth than CEL in vivo. This study first found that imidazoles linked to C-20 of CEL might affect its Michael addition, which will provide support of CEL or even the other Michael acceptors for the development as antitumor agents.

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