Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling |
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| Authors: | Jiangbo Wang Robert A. Mook Jiuyi Lu David M. Gooden Anthony Ribeiro Anchen Guo Larry S. Barak H. Kim Lyerly Wei Chen |
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| Affiliation: | 1. Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA;2. Duke Small Molecule Synthesis Facility, Department of Chemistry, Duke University, Durham, NC 27710, USA;3. Department of Radiology and Duke NMR Spectroscopy Center, Duke University, Durham, NC 27710, USA;4. Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA;5. Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA;6. Laboratory of Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, No. 6 Tiantanxili, Dongcheng District, Beijing 100050, China |
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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 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. |
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