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

Heat shock protein 70 (HSP70) and Heat shock protein 90 (HSP90) are essential molecular chaperones that function as central hubs in the cellular proteostasis network. They assist in the folding, stabilization, and assembly of a vast array of 'client' proteins, including many kinases and transcription factors critical for cell signaling and survival (1.2.1, 1.3.1). In cancer, these chaperones are frequently overexpressed to support the stability of mutated or overexpressed oncogenic proteins, thereby promoting tumor growth and resistance to therapy (1.3.4, 1.3.5). While HSP90 has been a primary focus for drug development, its inhibition often triggers a compensatory upregulation of HSP70, which provides cytoprotection and contributes to drug resistance (1.4.1, 1.4.5). Consequently, dual targeting of both HSP70 and HSP90 is an emerging therapeutic strategy to enhance anti-tumor efficacy and overcome resistance mechanisms (1.4.2). Beyond oncology, these proteins are vital in neurodegenerative diseases, where they modulate the aggregation and clearance of misfolded proteins such as tau and alpha-synuclein (1.2.3, 1.3.1).

Other names

70 kDa heat shock protein90 kDa heat shock proteinHSPA familyHSPC familyMolecular chaperonesStress proteins

Inhibition of the N-terminal or C-terminal ATPase activity to disrupt the chaperone cycle, leading to the destabilization and proteasomal degradation of oncogenic client proteins (e.g., HER2, Akt, BCR-ABL) and the induction of the heat shock response via HSF1 activation.