PT  - JOURNAL ARTICLE
AU  - Jay Singh
AU  - Bradley Tait
AU  - Naihsuan Guy
AU  - Jeffrey C. Sivils
AU  - David Culbertson
AU  - Chad Dickey
AU  - Szu Yu Kuo
AU  - Jason E. Gestwicki
AU  - Darren M. Hutt
AU  - Jane H. Dyson
AU  - Marc B. Cox
AU  - William E. Balch
TI  - Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone
AID  - 10.1101/412908
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 412908
4099  - http://biorxiv.org/content/early/2018/09/11/412908.short
4100  - http://biorxiv.org/content/early/2018/09/11/412908.full
AB  - The core cytosolic Hsp90 chaperone/co-chaperone complex plays a critical role in proteostasis management of human health and disease. To identify novel compounds that alter the ability of the Hsp90 co-chaperone Aha1 to modulate the ATPase activity found in multiple folding diseases ranging from steroid hormone receptor (SHR) sensitive prostate cancer to tauopathies associated with neurodegenerative diseases, we employed a high throughput screening (HTS) assay to monitor selectively Aha1-stimulated Hsp90 (ASH) ATPase activity. The ASH assay identified SEW04784 (SEW), a small molecule that disrupts ASH activity without inhibiting the basal Hsp90 ATPase activity. NMR analysis reveals that SEW binds to the C-terminal domain of Aha1 to disrupt its asymmetric binding to Hsp90 leading to abrogation of its chaperoning activity of Hsp90. SEW exhibits therapeutic potential by blocking the transcriptional activity of prostate cancer (PCa) associated variants of the androgen receptor (AR) in a cell-based model of PCa. Additionally, SEW exhibits the ability to clear toxic, phosphorylated tau aggregated species associated with tauopathies. By not directly impacting the basal ATPase function of the abundant and ubiquitous Hsp90, SEW could provide a therapeutic approach for mitigation of client-specific proteostatic disease.