Roughing up Smoothened

Roughing up Smoothened

Author: Scott Williams

The Smoothened (Smo) receptor has emerged in recent years as a validated drug target for the treatment of a range of Hedgehog-signaling-dependent tumors. These include skin cancer basal cell carcinoma (BCC) and the aggressive brain tumor medulloblastoma, which affects primarily children. The currently approved drug treatment aimed at this target is restricted to locally advanced or metastatic BCC and is limited by the emergence of resistance.

Research efforts by Stefan Peukert and colleagues, Novartis Institutes of Biomedical Research, Cambridge, MA, USA, identified a new class of Smo inhibitors that could overcome some of the current limitations, resulting in the discovery of NVP-LEQ506. This second-generation Smo antagonist combines high intrinsic potency, drug penetration to the brain, and activity against a resistant Smo mutant previously observed in a patient, all of which underscore its additional therapeutic potential. This drug candidate has shown excellent efficacy in rodent tumor models and is currently in phase I clinical trials.

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