Smoothened (SMO) is a GPCR-like receptor which, with Patched, mediates hedgehog signaling to regulate gene expression through the Gli transcription factors. Smoothened agonist (SAG) is a chlorobenzothiophene-containing compound which acts as a SMO agonist (EC50 = 3 nM) but inhibits hedgehog signaling at high concentrations (>1 μM). It directly binds to SMO and can block SMO inhibition by cyclopamine. Binding of SAG alters the conformation of SMO, leading to its accumulation in cilia and activation of gene transcription. At 15-240 nM, SAG prevents the neurotoxic effects of glucocorticoids without interfering with the beneficial effects of glucocorticoids on lung maturation. At higher concentrations (0.4 mM), SAG improves the conversion of human induced pluripotent stem cells to the neural lineage.
