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.
Smoothened (Smo) is a G-protein-coupled receptor that plays a pivotal role within the Hedgehog (HH) signaling pathway, which links to the formation of basal cell carcinoma, medulloblastoma, and other cancers. PF-5274857 is a highly selective SMO antagonist with IC50 values of 5.8 nM. In vitro, PF-5274857 specifically bound to Smo with Ki value of 4.6 nM. In addition, PF-5274857 completely inhibited Shh-induced Hh pathway activity with IC50 value of 2.7 nM measured by the transcriptional activity of Smo downstream gene Gli1 in MEF cells. In vivo, Oral administration of PF-5274857 at 1, 5, 10 and 30 mg/kg once daily for 6 days in the Ptch+/- p53+/- medulloblastoma allograft mice model with tumor group inhibition (TGI) of 39%, 80%, 119% and 133%, respectively. The above result suggested that PF-5274857 significant dose-dependent TGI and induced tumor regression at dose more than 10 mg/kg. PF-5274857 inhibited Gli1 mRNA transcription with IC50 values of 8.9 nM in the Ptch+/- p53+/- medulloblastoma allograft mice model. Oral administration of PF-5274857 at 30 mg/kg improved the survival rate in primary Ptch+/- p53-/- medulloblastoma mice. In addition, subcutaneous administration of PF-5274857 at 10 mg/kg showed approximately 40% of unbound PF527857 in the plasma was able to cross the blood-brain barrier in rats within 4 hours postdose[2].
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