J Pharmacol Exp Ther 2021 Sep 16;378(3):262-275. Epub 2021 Jun 16.
Neurodegeneration Cluster, Rare and Neurologic Disease Research TA (M.L.-G., N.M., E.G., C.V., V.R., D.I., L.P., V.T.), Integrated Drug Discovery (P.B., J.-F.S., D.M.), and DMPK (A.K.), Sanofi R&D, Chilly-Mazarin, France
In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR )/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2 (eIF2). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid- oligomers (AOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models. Read More