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

Cell Chem Biol. 2020 Mar 19;27(3):292-305.e6. doi: 10.1016/j.chembiol.2020.01.008. Epub 2020 Feb 3.

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.

Keywords: Aha1; Alzheimer disease; androgen receptor (AR); heat shock protein 90 (Hsp90); prostate cancer; tau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Molecular Chaperones / antagonists & inhibitors*
  • Molecular Chaperones / metabolism
  • Molecular Structure
  • Protein Folding / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*

Substances

  • HSP90 Heat-Shock Proteins
  • Molecular Chaperones
  • Small Molecule Libraries