Heat shock protein 90 and Heat shock protein 70 (HSP90/HSP70)

Heat shock protein 90 (HSP90) and heat shock protein 70 (HSP70) are essential molecular chaperones that collaborate within a sophisticated multichaperone complex to regulate protein homeostasis (proteostasis) [8, 15]. They facilitate the folding, maturation, and stabilization of a diverse set of "client" proteins, including many kinases, transcription factors, and steroid receptors [1, 12]. In cancer, this machinery is frequently overexpressed and hijacked to stabilize oncogenic proteins such as HER2, BCR-ABL, and AKT, thereby promoting tumor survival, proliferation, and resistance to therapy [2, 16]. In neurodegenerative diseases, the HSP90/HSP70 system is involved in the management of misfolded protein aggregates, such as tau and alpha-synuclein [17, 18]. Therapeutic targeting primarily focuses on HSP90 inhibitors, which disrupt the chaperone cycle and lead to the ubiquitin-proteasome-mediated degradation of client proteins [10, 12]. A characteristic pharmacodynamic effect of HSP90 inhibition is the compensatory induction of HSP70, which serves as a biomarker of target engagement but can also contribute to drug resistance [3, 14]. Recent drug development efforts have also explored HSP70 inhibitors and dual-targeting strategies to overcome these resistance mechanisms and improve therapeutic outcomes [14, 17]. Despite their potential, clinical progress has been challenged by toxicities such as hepatotoxicity and ocular damage associated with pan-inhibition of these ubiquitous proteins [13, 17].

Other names

HSP90/HSP70 multichaperone complexHSP90/HSP70 chaperone machineryHsp90-Hsp70-Hop complexHeat shock protein 90/70 system

Inhibition of the ATPase activity of the chaperone complex, typically by binding to the N-terminal ATP-binding domain of HSP90, which prevents the maturation of client proteins and triggers their degradation via the ubiquitin-proteasome pathway [10, 12].