PF-5274857Licensed by Pfizer 1373615-35-0

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Molecular Weight:

436.96 PF-5274857 is a potent and selective Smoothened (Smo) antagonist, inhibits Hedgehog (Hh) signaling with IC50 and Ki of 5.8 nM and 4.6 nM, respectively, and can penetrate the blood–brain barrier.

Biological Activity

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.


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.

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Product Categories : Stem Cells & Wnt > Hedgehog/Smoothened Inhibitor