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

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

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

Bioorg Med Chem. 2012 Nov 15;20(22):6751-7. doi: 10.1016/j.bmc.2012.09.030. Epub 2012 Sep 23.

PubMed ID

23063522 [ View in PubMed

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Abstract

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 beta-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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vismodegib	Smoothened homolog	Ki (nM)	16.2	N/A	N/A	Details