TY - JOUR
T1 - Brain-permeable small-molecule inhibitors of Hsp90 prevent α-synuclein oligomer formation and rescue α-synuclein-induced toxicity
AU - Putcha, Preeti
AU - Danzer, Karin M.
AU - Kranich, Lisa R.
AU - Scott, Anisa
AU - Silinski, Melanie
AU - Mabbett, Sarah
AU - Hicks, Carol D.
AU - Veal, James M.
AU - Steed, Paul M.
AU - Hyman, Bradley T.
AU - McLean, Pamela J.
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
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U2 - 10.1124/jpet.109.158436
DO - 10.1124/jpet.109.158436
M3 - Article
C2 - 19934398
AN - SCOPUS:77249101456
SN - 0022-3565
VL - 332
SP - 849
EP - 857
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -