PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a K(i) of 4.6 ± 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC(50) of 2.7 ± 1.4 nmol/L in cells. The μ-opioid receptor is weakly inhibited by PF-5274857 with a dissociation constant of 36 μM subsequently determined in a functional assay. PF-5274857 was orally available and metabolically stable in vivo. PF-5274857 shows significant dose-dependent tumor growth inhibition (TGI) and induces tumor regression at high doses(>10 mg/kg). PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hedgehog (Hh) signaling pathway. PF-5274857 is also able to cross the blood–brain barrier in rats within 4 hours post-dose.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 80 mg/mL
Water 80 mg/mL
Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier.
Rohner A, et al. Mol Cancer Ther. 2012 Jan;11(1):57-65. PMID: 22084163.
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