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

Abstract 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.