Small Molecule Antagonists in Distinct Binding Modes Inhibit Drug-Resistant Mutant of Smoothened

SummarySeveral small molecule antagonists for Smoothened (Smo) have been developed, and achieved promising preclinical efficacy in cancers that are dependent on Hedgehog (Hh) signaling. However, in a recent clinical study, a drug-resistant D473H SMO mutant was identified that is thought to be responsible for cancer relapse in a patient with medulloblastoma. Here, we report two Smo antagonists that bind to distinct sites, as compared to known antagonists and agonists, and inhibit both wild-type and mutant Smo. These findings provide an insight of the ligand-binding sites of Smo and a basis for the development of potential therapeutics for tumors with drug-resistant Smo mutations.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (106 K)Download as PowerPoint slideHighlights► New small molecule antagonists of Smo with distinct binding modes discovered from high throughput screens ► ALLO-1 and ALLO-2 are potent against the drug-resistant mutant of Smo ► ALLO-1 is potent against oncogenic mutant of Smo (SmoM2)