Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of smoothened

Chem Biol. 2011 Apr 22;18(4):432-7. doi: 10.1016/j.chembiol.2011.01.018.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm / genetics*
  • Hedgehog Proteins / antagonists & inhibitors
  • Humans
  • Mice
  • Mutant Proteins / antagonists & inhibitors*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Small Molecule Libraries / metabolism*
  • Small Molecule Libraries / pharmacology*
  • Smoothened Receptor

Substances

  • Hedgehog Proteins
  • Mutant Proteins
  • Receptors, G-Protein-Coupled
  • Small Molecule Libraries
  • Smo protein, mouse
  • Smoothened Receptor