title: Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened.
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.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Tao
authors.forename: Qihui
authors.initials: Q
authors.lastname: Jin
authors.forename: Dong-In
authors.initials: DI
authors.lastname: Koo
authors.forename: Xuebin
authors.initials: X
authors.lastname: Liao
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Englund
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Arun
authors.initials: A
authors.lastname: Ramamurthy
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.forename: Joseph
authors.initials: J
authors.lastname: Kelleher
authors.forename: Xu
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054852:Small Molecule Libraries / Q000378:metabolism* / Q000494:pharmacology*; D000072086:Smoothened Receptor
chemical_list: D053823:Hedgehog Proteins; D050505:Mutant Proteins; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; C491022:Smo protein, mouse; D000072086:Smoothened Receptor