Heat shock protein 90-Cdc37 chaperone complex (HSP90-CDC37 complex) (HSP90-CDC37 complex)

The Heat shock protein 90 (HSP90)-Cdc37 chaperone complex is a specialized molecular machinery essential for the folding, stabilization, and activation of a vast array of protein kinases, many of which are key drivers in oncogenesis (Taipale et al., 2010). HSP90 acts as the central hub of this system, while Cdc37 serves as a kinase-specific co-chaperone that recruits client kinases to the HSP90 cycle by recognizing the kinase domain (Verbaanderd et al., 2017). This complex is particularly critical in cancer cells, which often exhibit chaperone addiction to maintain the stability of mutated or overexpressed signaling proteins such as BRAF, HER2, and AKT (Neckers & Workman, 2012). By inhibiting the ATPase activity of HSP90 or disrupting its interaction with Cdc37, therapeutic agents can trigger the misfolding and subsequent proteasomal degradation of these client kinases (Smith & Workman, 2009). This multi-target approach makes the complex an attractive therapeutic target for overcoming resistance to single-kinase inhibitors in various malignancies. However, clinical development has faced significant hurdles, including off-target toxicities like retinal damage and the induction of a compensatory heat shock response that can limit efficacy (Bhatia et al., 2018).

Other names

HSP90-CDC37-kinase complexHsp90-Cdc37-client complexHsp90-Cdc37-kinase machineryHsp90-Cdc37-client kinase complex

Inhibition of the HSP90 ATPase cycle or physical disruption of the CDC37-HSP90 interaction, preventing the maturation of client kinases and promoting their proteasomal degradation.