Structural analogues of smoothened intracellular loops as potent inhibitors of Hedgehog pathway and cancer cell growth.

Smoothened is a critical component of the Hedgehog pathway that is essential for stem cell renewal and is dysregulated in many cancer types. We have found synthetic analogues of the second and third intracellular loops of smoothened to be potent inhibitors of the Hedgehog pathway. Palmitoylated peptides as short as 10 residues inhibited melanoma cells growth with IC50 in the low nanomolar range. The compounds are promising drug candidates and convenient tools for solving mechanisms of Hedgehog signaling.