1. Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone
- Author
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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, and Balch, William E
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Urologic Diseases ,Biotechnology ,Cancer ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Acquired Cognitive Impairment ,Dementia ,Prostate Cancer ,Alzheimer's Disease ,Brain Disorders ,Aging ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,HEK293 Cells ,HSP90 Heat-Shock Proteins ,Humans ,Molecular Chaperones ,Molecular Structure ,Protein Folding ,Small Molecule Libraries ,Aha1 ,Alzheimer disease ,androgen receptor ,heat shock protein 90 ,prostate cancer ,tau ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - 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.
- Published
- 2020