Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity.
Aggregation of alpha-synuclein (alphasyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and dementia with Lewy bodies. Lewy bodies contain alphasyn 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 alphasyn-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 alphasyn oligomerization and rescue toxicity. By use of this assay, we found that several compounds prevented alphasyn oligomerization as measured by decreased luciferase activity, led to a reduction in high-molecular-mass oligomeric alphasyn, and protected against alphasyn 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 EC(50) for inhibition of alphasyn oligomerization of approximately 48 nM and was able to rescue alphasyn-induced toxicity. In vivo assessment of SNX-0723 showed significant brain concentrations along with induction of brain Hsp70. With a low EC(50), brain permeability, and oral availability, these novel inhibitors represent an exciting new therapeutic strategy for PD.
Putcha
Preeti
P
Department of Neurology, Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Disease, 114 16th Street, Charlestown, MA 02129, USA.
Danzer
Karin M
KM
Kranich
Lisa R
LR
Scott
Anisa
A
Silinski
Melanie
M
Mabbett
Sarah
S
Hicks
Carol D
CD
Veal
James M
JM
Steed
Paul M
PM
Hyman
Bradley T
BT
McLean
Pamela J
PJ
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D002463:Cell Membrane Permeability; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014162:Transfection; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
C548545:2-fluoro-6-(tetrahydrofuran-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D051844:alpha-Synuclein; D062367:ortho-Aminobenzoates