Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling.

Journal Article (Journal Article)

The Hedgehog signaling pathway plays an essential role in embryo development and adult tissue homeostasis, in regulating stem cells and is abnormally activated in many cancers. Given the importance of this signaling pathway, we developed a novel and versatile high-throughput, cell-based screening platform using confocal imaging, based on the role of β-arrestin in Hedgehog signal transduction, that can identify agonists or antagonist of the pathway by a simple change to the screening protocol. Here we report the use of this assay in the antagonist mode to identify novel antagonists of Smoothened, including a compound (A8) with low nanomolar activity against wild-type Smo also capable of binding the Smo point mutant D473H associated with clinical resistance in medulloblastoma. Our data validate this novel screening approach in the further development of A8 and related congeners to treat Hedgehog related diseases, including the treatment of basal cell carcinoma and medulloblastoma.

Full Text

Duke Authors

Cited Authors

  • Wang, J; Mook, RA; Lu, J; Gooden, DM; Ribeiro, A; Guo, A; Barak, LS; Lyerly, HK; Chen, W

Published Date

  • November 15, 2012

Published In

Volume / Issue

  • 20 / 22

Start / End Page

  • 6751 - 6757

PubMed ID

  • 23063522

Pubmed Central ID

  • PMC3501270

Electronic International Standard Serial Number (EISSN)

  • 1464-3391

Digital Object Identifier (DOI)

  • 10.1016/j.bmc.2012.09.030


  • eng

Conference Location

  • England