Hedgehog (Hh) proteins, important regulators of development, bind the cell-surface protein Patched, allowing activation of the GPCR-like receptor, Smoothened (SMO). In vertebrates, this ultimately leads to the activation of the zinc-finger transcription factors of the Gli family. Overactivation of this pathway contributes to certain cancers. ALLO-1 is a SMO antagonist that inhibits both wild-type (IC50 = 50 nM) and mutant SMO, including the D473H SMO mutant (IC50s = 300-1000 nM). This compound binds to the SMO cysteine-rich domain, which is a different mechanism of interaction compared to other known SMO ligands that bind the transmembrane pocket.
