Brain-Permeable Small-Molecule Inhibitors of Hsp90 Prevent α-Synuclein Oligomer Formation and Rescue α-Synuclein-Induced Toxicity

Aggregation of alpha-synuclein (alpha syn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain alpha syn 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 alpha syn-induced 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 alpha syn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented alpha syn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric alpha syn, and protected against alpha syn 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 alpha syn oligomerization of approximately 48 nM and was able to rescue alpha syn-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.