PF-5274857 freebase

Research use only, not for human use.

PF-5274857 is an effective and selective hedgehog signaling pathway inhibitor (IC50: 5.8 nM and a Ki: 4.6 nM).

PF-5274857 is an effective and selective hedgehog signaling pathway inhibitor (IC50: 5.8 nM and a Ki: 4.6 nM). PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway.PF-5274857 was found to effectively penetrate the blood-brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. PF-5274857 was orally available and metabolically stable in vivo.

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.PF-5274857 shows less than 20% inhibition against a broad panel of protein kinases at 1 μM.

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.PF-5274857 (10 mg/kg; i.h.) in the plasma is able to cross the blood-brain barrier in rats within 4 hours postdose.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.PF-5274857 (30 mg/kg; p.o. once daily for 34 days) increases the survival rates of primary Ptch+/? p53?/? medulloblastoma mice.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 (T1/2) of 1.7±0.1 hours. Animal Model:Severe combined immunodeficient (SCID)-beige mice (6-8 weeks old) are genetically engineeredDosage:0, 1, 5, 10, 30 mg/kgAdministration:P.o. once daily for 6 days Result:Showed robust antitumor activity with an in vivo IC50 of 8.9±2.6 nM.Animal Model:Severe combined immunodeficient (SCID)-beige mice (6-8 weeks old)Dosage:0, 5, 10, 30 mg/kg (Pharmacokinetic Analysis)Administration:A single p.o.Result:The apparent volume of distribution of 5.6±0.5 L/kg; the half-life (T1/2) of 1.7±0.1 hours.

PF-5274857 | PF 5274857 | PF5274857

Wnt/Notch/Hedgehog

Smoothened (Smo)

smo

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1373615-35-0

436.96

C20H25ClN4O3S

>98% (HPLC)

DMSO:125 mg/mL?(286.07 mM;?Need ultrasonic)

CC1=CC(=C(N=C1)C2=CC(=NC=C2Cl)N3CCN(CC3)C(=O)CCS(=O)(=O)C)C

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(-20℃)

With Ice Pack

≥ 2 years