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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\u2010HSP90 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\u2010targeting agents can resensitize resistant tumors to kinase inhibitors. 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