Heat shock protein 90, cytosolic isoforms (HSP90)

Heat shock protein 90 (HSP90) is a ubiquitous and highly conserved molecular chaperone essential for the folding, stabilization, and maturation of over 400 'client' proteins (NIH, 1.1.3). In humans, the cytosolic isoforms consist of the stress-inducible HSP90α (encoded by HSP90AA1) and the constitutively expressed HSP90β (encoded by HSP90AB1) (UniProt P07900, P08238). These proteins function as ATP-dependent homodimers, utilizing energy from ATP hydrolysis to facilitate the conformational maturation of key signaling molecules, including kinases, transcription factors, and steroid receptors (Wikipedia, 1.4.2). In many diseases, particularly cancer, HSP90 is overexpressed and hijacked to stabilize mutated or overexpressed oncoproteins such as HER2, BCR-ABL, and mutant p53, thereby promoting cell survival and proliferation (NIH, 1.3.4). Therapeutic targeting of HSP90 involves small-molecule inhibitors like tanespimycin and ganetespib that typically bind to the N-terminal ATP-binding pocket, effectively halting the chaperone cycle (NIH, 1.3.1). This results in the simultaneous degradation of multiple oncogenic drivers through the ubiquitin-proteasome pathway, offering a potent multi-targeted approach (NIH, 1.3.3). Despite significant preclinical promise, the clinical advancement of HSP90 inhibitors has been hampered by challenges such as narrow therapeutic windows, off-target toxicities including ocular and hepatic effects, and the induction of the pro-survival heat shock response (NIH, 1.3.3, 1.5.3). Current research efforts are focused on developing isoform-selective inhibitors and identifying robust biomarkers, such as HER2 or ALK status, to better select patients who may benefit from these therapies (NIH, 1.5.1).

Other names

HSP90AA1HSP90AB1Heat shock protein 90 alphaHeat shock protein 90 betaHsp90αHsp90βHSPC1HSPC3HSP86HSP89AHeat shock protein 90 kDa alphaHeat shock protein 90 kDa beta

Inhibition of the N-terminal ATPase activity of HSP90, preventing the chaperone cycle and leading to the ubiquitin-proteasome degradation of client proteins (NIH, 1.3.1, 1.3.3).