2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO
Biological activity
Description
Target:
IC50 value: 5.8 nM
Target: Smoothened
In Vivo
PF-5274857 shows significant dose-dependent tumor growth inhibition (TGI) and induces tumor regression at high doses(>10 mg/kg)., PF-5274857 downregulates Gli1, Gli2, Ptch1, and Ptch2 gene expression levels to various degrees with maximal effects being achieved between 6 and 12 hours post-dose (Gli1 is the most sensitive gene), whereas PF-5274857 has little effect on Smo levels. In skin tissue, downregulation of Gli1 and Gli2 is also observed with a similar time course by PF-5274857. The model-derived drug concentration for half maximal inhibition of the tumor Gli1 mRNA production rate (IC50) by PF-5274857 is determined to be 8.9 nM in the Ptch+/?p53+/? medulloblastoma allograft mice, which mathematically corresponds to tumor regression of 119% TGI after 6 days of plasma exposure at this concentration. In the Ptch+/?p53?/? medulloblastoma allograft mice, the IC50 value is estimated to be 3.5 nM, consistent with the Ptch+/?p53+/? results. PF-5274857 is also able to cross the blood–brain barrier in rats within 4 hours post-dose [1].
In Vitro
PF-5274857 completely inhibits Shh-induced Hh pathway activity with IC50 of 2.7 nM measured by the transcriptional activity of Smo downstream gene Gli1 in MEF cells. The μ-opioid receptor is weakly inhibited by PF-5274857 with a dissociation constant of 36 μM subsequently determined in a functional assay [1].
Kinase Assay
Cell Assay
Animal Administration
References
[1]. Rohner A, et al. Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier. Mol Cancer Ther. 2012, 11(1), 57-65.
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