4.7 Article

Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor

期刊

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 149, 期 -, 页码 110-121

出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.02.034

关键词

Wnt signaling pathway; Hedgehog signaling pathway; Porcupine; Smoothened; Antagonist; Stem cell; Cancer therapy

资金

  1. National Natural Science Foundation of China [81473090, 81773561, 81473278]
  2. China Postdoctoral Science Foundation [2016M601884]
  3. Natural Science Foundation of Jiangsu Province [BK20140313, BM2013003]
  4. PAPD (Priority Academic Program Development of Jiangsu Higher Education Institutions)

向作者/读者索取更多资源

Embryonic stem cell pathways such as hedgehog and Wnt pathways are central to the tumorigenic properties of cancer stem cells (CSC). Since CSCs are characterized by their ability to self-renew, form differentiated progeny, and develop resistance to anticancer therapies, targeting the Wnt and hedgehog signaling pathways has been an important strategy for cancer treatment. Although molecules targeting either Wnt or hedgehog are common, to the best of our knowledge, those targeting both pathways have not been documented. Here we report a small molecule (compound 1) that inhibits both Wnt (IC50 = 0.5 nM) and hedgehog (IC50 = 71 nM) pathways based on reporter gene assays. We further identified that the molecular target of 1 for Wnt pathway inhibition was porcupine (a member of the membrane-bound O-acyltransferase family of proteins), a post-translational modification node in Wnt signaling; while the target of 1 mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary analysis of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound 1 demonstrated good oral exposure and bioavailability while eliciting no overt toxicity in mice. An important consideration in cancer treatment is the potential therapeutic escape through compensatory activation of an interconnected pathway when only one signaling pathway is inhibited. Toward this end, compound 1 may not only lead to the development of new therapeutics for Wnt and hedgehog related cancers, but may also help to develop potential cancer treatment which needs to target Wnt and hedgehog signaling simultaneously. (C) 2018 Elsevier Masson SAS. All rights reserved.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据