Robotnikinin takes on Sonic hedgehog

US researchers have discovered a potential inhibitor of the Hedgehog signalling pathway which they have dubbed ‘robotnikinin’, in honour of Sonic the hedgehog's nemesis, Dr Robotnik.

Robotnikinin, a macrocycle, was discovered when a Harvard University team used a small-molecule microarray to screen for molecules that bind to Sonic hedgehog, the most prominent protein in the pathway.

Sonic hedgehog is essential to embryonic development and in adults plays a role in stem cell division and in some cancers.

The hedgehog pathway is being intensely studied, particularly the roles of a receptor called Patched and a transducer called Smoothened. Several early stage clinical trials are underway involving antagonists of Smoothened in basal cell carcinoma and pancreatic cancer.

The Harvard team, led by Dr Stuart Schreiber, decided to look for modulators that act before Smoothened in the hedgehog pathway. Using the small-molecule microarray, they found a new macrocyle that bound directly to the Sonic hedgehog protein.

They tested it on human skin cells and a synthetic skin model and found that robotnikinin inhibits Sonic hedgehog signalling in a concentration-dependent manner.

When the Smoothened agonists purmorphamine and SAG were co-administered, it reversed the inhibitory effect.

The researchers conclude that robotnikinin will be valuable as a probe of diseases associated with aberrant hedgehog signalling.

Study co-author Lee Peng, of Harvard Medical School, said the team had a little fun with the naming rights to the molecule.

"As Sonic hedgehog was deliberately named after the Sega videogame character Sonic the hedgehog, we wished to adhere to the convention established by the original investigators in naming our inhibitor of Sonic hedgehog signalling," he said.

"Dr Robotnik is Sonic's archenemy, so we decided that 'robotnikinin' was an appropriate name for our compound."

Their findings are reported online in advance of publication in Nature Chemical Biology.