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Sonic hedgehog (Shh) signaling is initiated by binding of the ligand, Shh, to the receptor Patched 1, which relieves suppression by the associated receptor Smoothened (Smo). PF-05274857 is an antagonist which binds Smo (Ki = 4.6 nM), blocking Gli1 transcription in cells stimulated with Shh (IC50 = 2.7 nM). When administered orally, it distributes through plasma to skin and tumor and remains metabolically stable. PF-05274857 also penetrates the blood-brain barrier and inhibits Smo activity in the brain.

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