Therapeutics: Glycogen synthase kinase 3 β (GSK3B); microtubule-associated protein τ (tau; MAPT; FTDP-17)

In vitro and rodent studies identified an isonicotinamide-based GSK3β inhibitor that could help treat AD or other tauopathies. Chemical synthesis of isonicotinamide analogs and testing in competitive binding assays yielded a compound that inhibited GSK3β with an IC50 of 9.8 nM and was selective for GSK3β over 400 other kinases. In cell-based phosphorylation assays, the compound inhibited tau phosphorylation with an IC50 of 320 nM. In a mouse model of AD involving phosphorylated tau aggregates, the compound decreased tau phosphorylation compared with vehicle. In normal rats, the compound had brain-to-plasma ratios of 0.2-0.3 and a plasma clearance rate of 24 mL/min/kg. Next steps could include testing the compound in additional models of AD and other tauopathies.

Eli Lilly and Co. has LY2090314, a GSK3β inhibitor, in Phase II testing for acute leukemia and pancreatic cancer...