Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 20, Issue 22, Pages 6751-6757Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.09.030
Keywords
Hedgehog signaling; Smoothened; High-throughput screening; Smo antagonist; Smo mutation
Funding
- Pediatric Brain Tumor Foundation
- Clinical Oncology Research Center [5K12-CA100639-08]
- NIH
- NSF
- NC Biotechnology Center
- Duke University
- [5RO1 CA113656-03]
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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. (C) 2012 Elsevier Ltd. All rights reserved.
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