Smoothened (SMO) is a GPCR-like receptor which, with Patched, mediates hedgehog signaling to regulate gene expression through the Gli transcription factors. SANT 1 is a potent inhibitor of hedgehog signaling that acts by directly antagonizing SMO (IC50 = 20 nM). It counteracts SMO activation by the SMO agonist SAG but only partially competes with SAG binding to SMO. SANT 1 targets inactive SMO while it is in the cytoplasm, before it relocates to the primary cilium and is activated. Through antagonism of SMO, SANT 1 represses Gli-mediated transcription in a variety of cell types.
