PF-04802367 is a highly selective GSK-3 inhibitor with an IC50 of 2.1 nM based on a recombinant human GSK-3β enzyme assay and 1.1 nM based on ADP-Glo assay. It shows desirable central nervous system (CNS) properties and potency. It is equally effective at inhibition of the two known GSK-3 isoforms (GSK-3α and GSK-3β) with IC50 values of 10.0 and 9.0 nM in mobility shift assays, respectively.

GSK-3α:10 nM (IC50), GSK-3β:9 nM (IC50)

PF-04802367 (PF-367) effectively inhibits GSK-3β enzymatic activity in vitro, with ligand and lipophilic efficiency scores of 0.46 and 7.0, respectively [1]. It exhibits reasonable in vitro stability in human hepatic microsomes (t1/2=78.7 min) and has excellent passive permeability [1]. In a stable inducible CHO cell line over-expressing GSK-3β and its substrate tau, PF-367 inhibits phosphorylation of tau with an IC50 of 466 nM [1]. PF-367 demonstrates good cell viability (IC50 of 117 μM in THLE cytotoxicity assays) and an IC50 >100 μM in a hERG screening assay [1]. It shows significant right shifts against β-catenin translocation in HeLa cells with an EC50 of 6.2 μM, gene transcription in U2OS cells with an EC50 of 20.6 μM, and cell proliferation in HeLa cells as evaluated by Ki-67 incorporation with an EC50 of 9.0 μM [1].

PF-04802367 (PF-367) is a potent type-I dual GSK-3α/β inhibitor with exceptional kinome selectivity that modulates phosphorylated tau levels in vivo. It demonstrates dose-dependent inhibition of tau phosphorylation in the brain at subcutaneous doses of 1, 3.2, 10, 32, or 50 mg/kg. Additionally, PF-367 exhibits promising ADME properties, and robust CNS/peripheral p-Tau and muscle phosphorylated glycogen synthase (pGS) inhibition in vivo.