Heat shock protein 90 (HSP90) (HSP90)

Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone essential for the maturation, folding, and stability of a diverse set of client proteins, including oncogenic kinases, transcription factors, and steroid receptors (UniProt P07900). In many pathological states, particularly cancer, HSP90 is overexpressed or hijacked to maintain the proteostasis of mutated or overexpressed signaling proteins that drive disease progression (PMID: 16968725). Celastrol, a pentacyclic triterpene derived from the 'Thunder God Vine,' is a potent modulator of the heat shock response that specifically targets the HSP90-Cdc37 co-chaperone complex (PMID: 19114704). By disrupting this interaction, Celastrol promotes the ubiquitin-mediated degradation of client proteins such as Akt, CDK4, and HER2, leading to cell cycle arrest and apoptosis in malignant cells (PubChem CID 122724). Furthermore, Celastrol induces the activation of Heat Shock Factor 1 (HSF1), which triggers the expression of cytoprotective chaperones like HSP70, offering potential therapeutic benefits in neurodegenerative diseases characterized by protein misfolding (PMID: 26004070). Despite its broad pharmacological activity, the clinical utility of Celastrol and other HSP90 inhibitors is often constrained by systemic toxicity and potential hepatotoxicity (PMID: 29635134).

Other names

HSP90Heat shock protein 90kDaHSPCAHSPCBMolecular chaperone HSP90HSP90AA1HSP90AB1HSP90N

Celastrol acts as an allosteric inhibitor of the Heat shock protein 90 (HSP90) by disrupting its association with the co-chaperone Cdc37, which is specifically required for the loading of protein kinases onto the HSP90 complex (PMID: 19114704). This disruption leads to the misfolding and subsequent proteasomal degradation of key oncogenic client proteins (PMID: 16968725). Additionally, Celastrol induces the heat shock response by promoting the phosphorylation and trimerization of Heat Shock Factor 1 (HSF1), leading to the upregulation of other molecular chaperones such as HSP70 and HSP40 (PubChem CID 122724).