Zhang X, Hernandez I, Rei D, Mair W, Laha JK, Cornwell ME, Cuny GD, Tsai LH, Steen JA, Kosik KS.
J Biol Chem. 2013 Jul 26;288(30):22042-56. doi: 10.1074/jbc.M112.436402. Epub 2013 Jun 4.
Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3β. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3β in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3×Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3β to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.
http://www.jbc.org/content/288/30/22042.longUniversity of California at Santa Barbara
United States
