PF-5274857

PF-5274857 is a potent, selective, orally active and brain-penetrant antagonist of Smo, with an IC₅₀ of 5.8 nM and K_i of 4.6 nM. PF-5274857 has potential for research of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway^[1]. IC50 & Target: IC50: 5.8 nM (Smo); Ki: 4.6 nM (Smo)^[1] In Vitro: PF-5274857 completely inhibits Shh-induced Hh pathway activity with an IC₅₀ of 2.7±1.4 nM measured by the transcriptional activity of Smo downstream gene Gli1 in MEF cells^[1].
PF-5274857 shows less than 20% inhibition against a broad panel of protein kinases at 1 μM^[1]. In Vivo: PF-5274857 (1-30 mg/kg; p.o. once daily for 6 days) shows robust antitumor efficacy and correlation between PK and PD in medulloblastoma allograft mice models^[1].
PF-5274857 (10 mg/kg; i.h.) in the plasma is able to cross the blood-brain barrier in rats within 4 hours postdose^[1].
PF-5274857 (10-100 mg/kg; p.o. once daily for 4 days) is able to target Smo in the brain leading to the downregulation of Hh pathway activity in the brain tumor^[1].
PF-5274857 (30 mg/kg; p.o. once daily for 34 days) increases the survival rates of primary Ptch^+/? p53^?/? medulloblastoma mice^[1].
PF-5274857 (5-30 mg/kg; p.o.) exhibits the apparent volume of distribution of 5.6±0.5 L/kg and the half-life (T_1/2) of 1.7±0.1 hours^[1].