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Published on: September 20, 2016
Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened
Haiyan Tao1, Qihui Jin, Dong-In Koo
1Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
Abstract:
Several 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.
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