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1 mg
5 mg
10 mg
1 mM
2.2885 mL
11.4427 mL
22.8854 mL
5 mM
0.4577 mL
2.2885 mL
4.5771 mL
10 mM
0.2289 mL
1.1443 mL
2.2885 mL
50 mM
0.0458 mL
0.2289 mL
0.4577 mL
Description
PF-5274857 is a potent and selective antagonist, inhibits (Hh) signaling with and of 5.8 nM and 4.6 nM, respectively, and can penetrate the blood–brain barrier.
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.
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 Ptchp53 medulloblastoma allograft mice, which mathematically corresponds to tumor regression of 119% TGI after 6 days of plasma exposure at this concentration. In the Ptchp53 medulloblastoma allograft mice, the IC50 value is estimated to be 3.5 nM, consistent with the Ptchp53 results. PF-5274857 is also able to cross the blood–brain barrier in rats within 4 hours post-dose.
