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Identification of a novel Smoothened antagonist that potently suppresses Hedgehog signaling

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收录情况： ◇ SCIE

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机构： [1]Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA; [2]Duke Univ, Dept Chem, Duke Small Mol Synth Facil, Durham, NC 27710 USA; [3]Duke Univ, Dept Radiol, Durham, NC 27710 USA; [4]Duke Univ, Duke NMR Spect Ctr, Durham, NC 27710 USA; [5]Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA; [6]Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA; [7]Capital Med Univ, Beijing Tiantan Hosp, Lab Clin Med Res, Beijing 100050, Peoples R China

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关键词： Hedgehog signaling Smoothened High-throughput screening Smo antagonist Smo mutation

摘要：

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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出版当年[2011]版：

大类 | 3 区医学

小类 | 3 区生化与分子生物学 3 区药物化学 3 区有机化学

最新[2023]版：

大类 | 3 区医学

小类 | 2 区有机化学 3 区生化与分子生物学 3 区药物化学

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出版当年[2010]版：

Q2 CHEMISTRY, ORGANIC Q2 CHEMISTRY, MEDICINAL Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

最新[2023]版：

Q1 CHEMISTRY, ORGANIC Q2 CHEMISTRY, MEDICINAL Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Q3 CHEMISTRY, MEDICINAL

影响因子： 3.3 最新[2023版] 3.1 最新五年平均 2.978 出版当年[2010版] 3.108 出版当年五年平均 2.822 出版前一年[2009版] 2.921 出版后一年[2011版]

第一作者：

第一作者机构： [1]Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA;

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通讯机构： [1]Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA;

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