Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone. Issue 3 (19th March 2020)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Cell chemical biology. Volume 27:Issue 3(2020)
• Page Start: 292
• Page End: 305.e6
• Publication Date: 2020-03-19
• Subjects: heat shock protein 90 (Hsp90) -- Aha1 -- tau -- Alzheimer disease -- androgen receptor (AR) -- prostate cancer; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2020.01.008
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: HTS identifies SEW84, a novel inhibitor of the Aha1-stimulated Hsp90 ATPase activity SEW84 does not affect the basal ATPase activity of Hsp90 SEW84 reduces the expression and trophic activity of PCa-linked AR variants SEW84 specifically clears phosphorylated tau Abstract : Singh et al . identified SEW84 as an inhibitor of the stimulated Hsp90 activity. SEW84 is able to reduce the expression and activity of androgen receptor variants associated with prostate cancer. SEW84 preferentially clears phosphorylated, aggregation-prone Tau, found in a number of neurodegenerative diseases, such as Alzheimer disease.