Management of Hsp90-Dependent Protein Folding by Small Molecules Targeting the Aha1 Co-Chaperone

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.