A new molecule called ‘robotnikinin’ stops the Hedgehog signaling pathway, which is critical in embryonic development, using a previously unknown mechanism, reports a paper online this week in Nature Chemical Biology. As well as being important in embryonic development the Hedgehog signaling pathway has been implicated in a number of cancers and the discovery of robotnikin may provide an alternative avenue for cancer drugs discovery.
A number of chemical modulators of the Hedgehog signaling pathway have been discovered, but all act on a protein receptor called Smoothened, or at later points in the pathway. To discover pathway modulators that act by a new mechanism, Stuart Schreiber, Lee Peng and colleagues used a small-molecule microarray?a glass microscope slide with a wide array of chemicals attached?to screen for small molecules that bound to a portion of the Hedgehog protein itself. This led the team to discover the chemical robotnikinin. As expected for a Hedgehog-binding molecule, robotnikinin was shown to act before Smoothened in the signaling pathway. The authors further showed that this small molecule blocked Hedgehog signaling in primary human skin cells and in a synthetic model of human skin.
Clinical trials with Smoothened antagonists are currently underway. The discovery of robotnikinin provides an alternative cancer drug lead and an example of a new way to halt Hedgehog signaling.