Heat shock protein 90 family (Hsp90)

The Heat shock protein 90 (Hsp90) family comprises a group of highly conserved molecular chaperones essential for the folding, stabilization, and maturation of a wide array of "client" proteins involved in signal transduction, cell cycle regulation, and proteostasis [1, 3, 5]. In humans, the family includes four major members: the cytosolic isoforms Hsp90α (inducible) and Hsp90β (constitutive), the endoplasmic reticulum-resident GRP94 (HSP90B1), and the mitochondrial TRAP1 [1, 13]. These proteins function as ATP-dependent dimers, utilizing their N-terminal ATPase activity to drive a conformational cycle that facilitates the proper assembly of client proteins, many of which are key oncoproteins like HER2, Akt, and B-Raf [5, 10]. Because cancer cells rely heavily on Hsp90 to maintain the stability of these mutated or overexpressed signaling molecules, Hsp90 has emerged as a significant therapeutic target in oncology [1, 17]. Numerous small-molecule inhibitors, such as tanespimycin and ganetespib, have been developed to target the ATP-binding pocket of Hsp90, leading to the degradation of client proteins via the ubiquitin-proteasome pathway [11, 15]. Despite their potential, the clinical development of Hsp90 inhibitors has faced challenges, including dose-limiting toxicities such as ocular and hepatotoxicity, as well as the induction of a compensatory heat shock response that can promote drug resistance [11, 14].

Other names

Hsp90 familyHSPC familyHsp90 chaperone familyHeat shock 90kDa protein familyHSP90AA1HSP90AB1HSP90B1TRAP1

Hsp90 inhibitors primarily act through ATP-competitive binding to the N-terminal domain (NTD) of the protein, which halts the chaperone cycle and prevents the maturation of client proteins. This leads to the misfolding of these clients, which are subsequently ubiquitinated and degraded by the 26S proteasome. Some inhibitors also target the C-terminal domain (CTD) to disrupt dimerization and co-chaperone interactions.