Ma, Haikuo; Chen, Qin; Zhu, Fang; Zheng, Jiyue; Li, Jiajun; Zhang, Hongjian; Chen, Shuaishuai; Xing, Haimei; Luo, Lusong; Zheng, Long Tai; He, Sudan; Zhang, Xiaohu published the artcile< Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor>, Reference of 660867-80-1, the main research area is Wnt hedgehog signaling inhibitor antitumor neoplasm pharmacokinetics; Antagonist; Cancer therapy; Hedgehog signaling pathway; Porcupine; Smoothened; Stem cell; Wnt signaling pathway.
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 mols. targeting either Wnt or hedgehog are common, to the best of the knowledge, those targeting both pathways have not been documented. Here the authors report a small mol. (compound I) that inhibits both Wnt (IC50 = 0.5 nM) and hedgehog (IC50 = 71 nM) pathways based on reporter gene assays. The authors further identified that the mol. target of I for Wnt pathway inhibition was porcupine (a member of the membrane-bound O-acyltransferase family of proteins), a posttranslational modification node in Wnt signaling; while the target of I mitigating hedgehog pathway was Smoothened, a key G protein coupled receptor (GPCR) mediating hedgehog signal transduction. Preliminary anal. of structure-activity-relationship identified key functional elements for hedgehog/Wnt inhibition. In in vivo studies, compound I 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 I 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.
European Journal of Medicinal Chemistry published new progress about Antitumor agents. 660867-80-1 belongs to class alcohols-buliding-blocks, and the molecular formula is C12H18BNO2, Reference of 660867-80-1.
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