Discovery of small-molecule modulators of the Sonic Hedgehog pathway

J Am Chem Soc. 2013 Jul 3;135(26):9675-80. doi: 10.1021/ja400034k. Epub 2013 Jun 25.

Abstract

The Hedgehog signaling pathway is involved in the development of multicellular organisms and, when deregulated, can contribute to certain cancers, among other diseases. The molecular characterization of the pathway, which has been enabled by small-molecule probes targeting its components, remains incomplete. Here, we report the discovery of two potent, small-molecule inhibitors of the Sonic Hedgehog (Shh) pathway, BRD50837 and BRD9526. Both compounds exhibit stereochemistry-based structure-activity relationships, a feature suggestive of a specific and selective interaction of the compounds with as-yet-unknown cellular target(s) and made possible by the strategy used to synthesize them as members of a stereochemically and skeletally diverse screening collection. The mechanism-of-action of these compounds in some ways shares similarities to that of cyclopamine, a commonly used pathway inhibitor. Yet, in other ways their mechanism-of-action is strikingly distinct. We hope that these novel compounds will be useful probes of this complex signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Hedgehog Proteins / antagonists & inhibitors*
  • Hedgehog Proteins / metabolism
  • Mice
  • Molecular Structure
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship

Substances

  • Hedgehog Proteins
  • Shh protein, mouse
  • Small Molecule Libraries