학술논문
Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone
Document Type
article
Author
Singh, Jay K; Hutt, Darren M; Tait, Bradley; Guy, Naihsuan C; Sivils, Jeffrey C; Ortiz, Nina R; Payan, Ashley N; Komaragiri, Shravan Kumar; Owens, Jazzmin Jovonna; Culbertson, David; Blair, Laura J; Dickey, Chad; Kuo, Szu Yu; Finley, Dan; Dyson, H Jane; Cox, Marc B; Chaudhary, Jaideep; Gestwicki, Jason E; Balch, William E
Source
Cell Chemical Biology. 27(3)
Subject
Language
Abstract
Hsp90 plays an important role in health and is a therapeutic target for managing misfolding disease. Compounds that disrupt co-chaperone delivery of clients to Hsp90 target a subset of Hsp90 activities, thereby minimizing the toxicity of pan-Hsp90 inhibitors. Here, we have identified SEW04784 as a first-in-class inhibitor of the Aha1-stimulated Hsp90 ATPase activity without inhibiting basal Hsp90 ATPase. Nuclear magnetic resonance analysis reveals that SEW84 binds to the C-terminal domain of Aha1 to weaken its asymmetric binding to Hsp90. Consistent with this observation, SEW84 blocks Aha1-dependent Hsp90 chaperoning activities, including the in vitro and in vivo refolding of firefly luciferase, and the transcriptional activity of the androgen receptor in cell-based models of prostate cancer and promotes the clearance of phosphorylated tau in cellular and tissue models of neurodegenerative tauopathy. We propose that SEW84 provides a novel lead scaffold for developing therapeutic approaches to treat proteostatic disease.