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.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.