Browsing by Author "Zhang, Xuemei"
Now showing 1 - 2 of 2
- Results Per Page
- Sort Options
Item Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models(Journal of BIological Chemistry, 2013-07) Zhang, Xuemei; Hernandez, Israel; Rei, Damien; Mair, Waltraud; Laha, Joydev K.; Cornwell, Madison E.; Cuny, Gregory D.; Tsai, Li-Huei; Steen, Judith A. J.; Kosik, Kenneth S.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 GSK3?. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3? 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 GSK3? to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting.Item Structure–activity relationship study of 2,4-diaminothiazoles as Cdk5/p25 kinase inhibitors(Bioorganic and Medicinal Chemistry Letters, 2012-04) Laha, Joydev K.; Zhang, Xuemei; Qiao, Lixin; Chatterjee, Snigdha; Robinson, Shaughnessy; Kosik, Kenneth S.; Cuny, Gregory D.Cdk5/p25 has emerged as a principle therapeutic target for numerous acute and chronic neurodegenerative diseases, including Alzheimer’s disease. A structure–activity relationship study of 2,4-diaminothiazole inhibitors revealed that increased Cdk5/p25 inhibitory activity could be accomplished by incorporating pyridines on the 2-amino group and addition of substituents to the 2- or 3-position of the phenyl ketone moiety. Interpretation of the SAR results for many of the analogs was aided through in silico docking with Cdk5/p25 and calculating protein hydrations sites using WaterMap. Finally, improved in vitro mouse microsomal stability was also achieved.