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

The Heat shock protein 70 (HSP70) and 90 (HSP90) families are essential molecular chaperones that function as a coordinated machinery to maintain cellular proteostasis. HSP70 typically assists in the early folding of nascent polypeptides and the refolding of denatured proteins, while HSP90 specializes in the late-stage maturation and stabilization of a specific set of 'client' proteins, many of which are key signaling transducers. In oncology, these chaperones are frequently overexpressed to stabilize mutated or overexpressed oncoproteins, such as HER2, BCR-ABL, and AKT, which are vital for cancer cell survival and proliferation. In neurodegenerative disorders, the HSP70/90 complex plays a critical role in managing the aggregation of toxic proteins like tau and alpha-synuclein. Therapeutic targeting of these families primarily involves small-molecule inhibitors that bind to their ATP-binding domains, thereby disrupting their chaperone function and triggering the degradation of oncogenic clients. While HSP90 inhibitors have reached clinical trials and one (Pimitespib) has achieved regulatory approval, challenges such as ocular toxicity and the compensatory induction of cytoprotective HSP70 remain significant hurdles in drug development.

Other names

HSPA familyHSPC familyHeat shock protein 70kDaHeat shock protein 90kDaMolecular chaperonesChaperomeHSP70/HSP90 multichaperone complex

Inhibition of the N-terminal ATP-binding site to disrupt ATPase activity and the chaperone cycle, leading to the ubiquitin-proteasome-mediated degradation of client proteins and induction of the heat shock response via HSF1 activation.