GSK3β-IN-4 is a selective, potent, orally active ATP-competitive inhibitor of GSK3β, with an IC50 value of 0.37 nM. It also inhibits GSK3α with an IC50 of 2.75 nM and a selectivity index (SI) of 7.4. By inhibiting GSK3β, GSK3β-IN-4 reduces tau protein phosphorylation at the Ser396 site and improves cognitive deficits in Alzheimer's disease models. This compound is applicable for Alzheimer's research.

GSK-3β:0.37 nM

GSK3β-IN-4 (Compound 39a) effectively inhibits the phosphorylation of Tau at the Ser396 site in Tau (P301L) 293T cells, with an EC50 of 0.06 μM and exhibits low cytotoxicity (IC50 = 80.75 μM). Under ATP concentrations of 1 × Km, 10 × Km, and 100 × Km, the IC50 values for GSK3β are 1.27 nM, 7.14 nM, and 77.8 nM, respectively, indicating an ATP-competitive inhibition mode.

GSK3β-IN-4 (Compound 39a) administered orally at 1000 mg/kg as a single dose is non-lethal to C57BL/6J mice, with normal weight gain over 14 days, no behavioral abnormalities, and no pathological damage in major organs. Administering GSK3β-IN-4 at 5-25 mg/kg orally once daily for 14 days improves cognitive deficits and reduces Tau Ser396 phosphorylation in an Okadaic acid-induced Alzheimer's mouse model. Moreover, a daily oral dosage of 5 mg/kg of GSK3β-IN-4 over 60 days enhances spatial learning and memory in 6-month-old 3×Tg-AD mice, decreases Tau Ser396 phosphorylation in the hippocampal CA3 region, and shows efficacy comparable to Donepezil (5 mg/kg), without affecting motor function.