PF-04802367

PF-04802367 (PF-367) 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.?PF-04802367 shows desirable central nervous system (CNS)?properties and potency. PF-04802367 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^[1]. In Vitro: PF-04802367 (PF-367) is efficient at inhibiting GSK-3β enzymatic activity?in vitro?with ligand and lipophilic efficiency scores of 0.46 and 7.0, respectively^[1].
PF-367 has reasonable?in vitro?stability in human hepatic microsomes (t_1/2=78.7 min), has excellent passive permeability^[1].
In a stable inducible CHO cell line over-expressing GSK-3β and its substrate tau, PF-367 inhibited phosphorylation of tau with an IC₅₀?of 466 nM^[1].
PF-367 has good cell viability (IC₅₀?of 117 μM in THLE cytotoxicity assays) and an IC₅₀?>100 μM in a hERG screening assay^[1].
PF-367 shows significant right shifts against β-catenin translocation in HeLa cells with EC₅₀?of 6.2 μM, gene transcription in U20S cells with EC₅₀?of 20.6 μM, and cell proliferation in HeLa cells as evaluated by Ki-67 incorporation with EC₅₀?of 9.0 μM^[1]. In Vivo: PF-04802367 (PF-367) a potent GSK-3 inhibitor with exceptional kinome selectivity that modulates phosphorylated tau levels?in vivo.?Inhibition of phosphorylation of tau in brain by PF-367 (A single subcutaneous of 1, 3.2, 10, 32 or 50 mg/kg) is dose-dependent^[1].
PF-04802367 (PF-367), a potent type-I dual GSK-3α/β?inhibitor, showing promising absorption; distribution, metabolism and elimination (ADME) properties combined with robust CNS/peripheral p-Tau and muscle phosphorylated glycogen synthase (pGS) inhibition in vivo^[2].