Brain-permeable small-molecule inhibitors of Hsp90 prevent α-synuclein oligomer formation and rescue α-synuclein-induced toxicity

Preeti Putcha, Karin M. Danzer, Lisa R. Kranich, Anisa Scott, Melanie Silinski, Sarah Mabbett, Carol D. Hicks, James M. Veal, Paul M. Steed, Bradley T. Hyman, Pamela J. McLean

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Aggregation of α-synuclein (αsyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain αsyn and several heat shock proteins (Hsp), a family of molecular chaperones up-regulated by the cell under stress. We have previously shown that direct expression of Hsp70 and pharmacological up-regulation of Hsp70 by geldanamycin, an Hsp90 inhibitor, are protective against αsyninduced toxicity and prevent aggregation in culture. Here, we use a novel protein complementation assay to screen a series of small-molecule Hsp90 inhibitors for their ability to prevent αsyn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented αsyn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric αsyn, and protected against αsyn cytotoxicity. A lead compound, SNX-0723 (2-fluoro-6-[(3S)-tetrahydrofuran-3- ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide) was determined to have an EC50 for inhibition of αsyn oligomerization of approximately 48 nM and was able to rescue αsyn-induced toxicity. In vivo assessment of SNX-0723 showed significant brain concentrations along with induction of brain Hsp70. With a low EC50, brain permeability, and oral availability, these novel inhibitors represent an exciting new therapeutic strategy for PD.

Original languageEnglish (US)
Pages (from-to)849-857
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number3
DOIs
StatePublished - Mar 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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