Heat shock protein 90–cell division cycle 37 complex (Hsp90–Cdc37 complex)

The heat shock protein 90–cell division cycle 37 complex is a molecular chaperone system critical for the folding, stabilization, and activation of a broad range of kinases, particularly protein kinases involved in signal transduction and cell cycle regulation[1][2][3][4][5]. Hsp90 is an ATP-dependent chaperone, and Cdc37 acts as a co-chaperone, serving as an adaptor that selectively recruits protein kinase clients to Hsp90[1][2][4][5]. Cdc37 binds both the N-terminal domain of client kinases and the middle domain of Hsp90, stabilizing kinases in a partially unfolded state to enable their subsequent activation and functional maturation in response to Hsp90's ATP cycle[2][3][5]. This complex is essential for the stability and activity of many oncogenic kinases, rendering it a validated therapeutic target, especially in cancer, where its disruption leads to degradation of multiple driver kinases and impaired signaling pathways relevant to tumor growth and survival[1][2]. Inhibitors targeting Hsp90 or the Hsp90–Cdc37 interaction are under investigation for cancer therapy, but clinical development has been limited by toxicity and a broad impact on many cellular proteins[2][5]. The complex also plays roles in other diseases where kinase homeostasis is perturbed, and its activity or substrate spectrum can be monitored through levels or phosphorylation status of client proteins[4][5].

Other names

HSP90–CDC37 complexHSP90–Cdc37 chaperone complex

Inhibition of Hsp90 ATPase activity disables client kinase maturation and refolding, leading to proteasomal degradation of oncogenic kinases and impaired signaling - Disruption of Hsp90–Cdc37 interaction, thereby blocking protein kinase client recruitment and stabilization