Advances in small-molecule inhibitors targeting Hsp90-Cdc37 protein-protein interaction

Heat shock protein 90(Hsp90)which is a molecular chaperone that integrates multiple oncogenic pathways, is an important target in cancer therapy. The present research and development of the traditional N-terminal and C-terminal inhibitors has been restricted while targeting Hsp90 and cell division cycle protein Cdc37 has become the new direction of inhibiting Hsp90. Previous studies have demonstrated that various protein kinases rely on Cdc37 to load onto Hsp90 to complete their correct folding. Thus targeting Hsp90-Cdc37 is a promising strategy to inhibit protein kinases and alleviate the side effects. The interaction mechanism between Hsp90 and Cdc37 has become clearer in recent studies and many natural products have been reported to possess the ability to disassociate Hsp90-Cdc37. In this review, current knowledge on these small molecule inhibitors are summarized. The mode of action is also discussed as the references for the development of novel Hsp90 inhibitors.