Small Molecule Stops Cancer-Related Hedgehog Protein

If you want to stop cancer, it may be best to stop a hedgehog first, a new study finds. Stuart L. Schreiber of the Broad Institute and Harvard University and coworkers report having identified robotnikinin, the first small molecule that binds and inhibits Sonic hedgehog, a signaling protein that plays key roles in development and cancer (Nat. Chem. Biol., DOI: 10.1038/nchembio.142). Other compounds that inhibit hedgehog signaling have been developed, and some are in drug trials, but they interact not with the hedgehog protein itself but with Smoothened, a transmembrane receptor in a downstream part of the signaling pathway. Schreiber and coworkers attempted something a lot more difficult—finding a small molecule that blocks the protein-protein interaction between hedgehog and its direct target, either a receptor called Patched or an auxiliary coreceptor. Blocking hedgehog signaling at two possible sites, Smoothened and Patched, “increases the probability of at least one of them being successful,” Schreiber says. Animal studies of robotnikinin “have yielded encouraging early results” that could open the way to human clinical investigations, Schreiber notes.