Allosteric CDC37 Inhibitor Disrupts Chaperone Complex to Block CDK4/6 Maturation

Cell division cycle 37 (CDC37) is a member of the molecular chaperone family and acts as a cochaperone of heat shock protein 90 (HSP90), which is overexpressed in many Cancer types as a regulator of protein kinase maturation. In this process, CDC37 selectively recognizes and stabilizes protein kinases by forming a HSP90-CDC37-kinase chaperone complex. The protein-protein interactions (PPIs) of HSP90-CDC37 and CDC37-kinase complexes contribute to malignant tumors, as oncogenic kinases in malignant cells depend upon CDC37 expression. Thus, inhibiting CDC37 to disrupt HSP90-CDC37-kinase chaperone complex reveals as a promising way to achieve selective inhibition of oncogenic kinase maturation. Herein, we report a small-molecule CDC37 inhibitor called DDO-6079 that simultaneously inhibits HSP90-CDC37 and CDC37-CDK4/6 chaperone complex by binding to an allosteric site on CDC37. DDO-6079 selectively inhibited the maturation of multiple oncogenic kinases to escape heat shock response (HSR). Furthermore, DDO-6079 decreased the thermostability of CDK6, reversed the resistance of CDK6 to palbociclib (a successful CDK4/6 inhibitor) in colorectal Cancer cells and exhibited efficacy in vivo. Together, the results revealed that DDO-6079 is a first-in-class small molecule CDC37 inhibitor that disrupts the HSP90-CDC37-kinase chaperone complex and provides a new way to block kinase maturation.

CDC37 inhibition; HSP90-CDC37-CDK4/6; allosteric inhibition; drug resistance; molecular chaperone; protein-protein interaction.