PF-5274857 freebase

SKU: orb1218884

Description

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.

Key Properties

• CAS Number: 1373615-35-0
• MW: 436.96
• Purity: >98% (HPLC)
• Formula: C₂₀H₂₅ClN₄O₃S
• SMILES: CC1=CC(=C(N=C1)C2=CC(=NC=C2Cl)N3CCN(CC3)C(=O)CCS(=O)(=O)C)C
• Target: Smoothened (Smo)
• Solubility: DMSO:125 mg/mL (286.07 mM; Need ultrasonic)

Bioactivity

• 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. 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 engineered. Dosage: 0, 1, 5, 10, 30 mg/kg. Administration: 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.
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• 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. PF-5274857 shows less than 20% inhibition against a broad panel of protein kinases at 1 μM.
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Storage & Handling

• Storage: Storage temperature: -20°C. Stability: ≥ 2 years
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

PF-5274857 | PF 5274857 | PF5274857

Quick Database Links

Gene Symbol

Smoothened (Smo)