Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor
Autor: | Lusong Luo, Shuaishuai Chen, Haimei Xing, Sudan He, Haikuo Ma, Jiajun Li, Long Tai Zheng, Hongjian Zhang, Qin Chen, Xiaohu Zhang, Jiyue Zheng, Fang Zhu |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Antineoplastic Agents Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Cancer stem cell Drug Discovery Animals Humans Hedgehog Proteins Wnt Signaling Pathway Hedgehog G protein-coupled receptor Pharmacology Chemistry Organic Chemistry Wnt signaling pathway Membrane Proteins General Medicine Smoothened Receptor Hedgehog signaling pathway Cell biology 030104 developmental biology Drug Design 030220 oncology & carcinogenesis Signal transduction Stem cell Smoothened Acyltransferases Signal Transduction |
Zdroj: | European Journal of Medicinal Chemistry. 149:110-121 |
ISSN: | 0223-5234 |
DOI: | 10.1016/j.ejmech.2018.02.034 |
Popis: | 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. |
Databáze: | OpenAIRE |
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