Targeting Cell division cycle 37: A Promising Novel Therapeutic Strategy

Cell division cycle 37 (CDC37) is a kinase-specific HSP90 cochaperone that stabilizes oncogenic kinases and is frequently overexpressed in malignancies, making it a compelling therapeutic target. Herein, we systematically delineate therapeutic strategies aimed at inhibiting CDC37, including modulating its Ser13 phosphorylation switch through CK2 inhibition or PP5 activation, disrupting the CDC37-HSP90 complex, and blocking its interaction with kinase clients. These approaches culminate in the concerted degradation of multiple kinase client proteins. CDC37 inhibitors induce cell cycle arrest and apoptosis in models of colon cancer, prostate cancer, and others. Critically, by disrupting the thermal stability of kinases, CDC37-targeting agents can resensitize resistant tumors to kinase inhibitors. In summary, targeting CDC37 is not only a novel anticancer strategy but also a paradigm-shifting approach to address the persistent challenge of kinase inhibitor resistance.