1189816-87-2Relevant articles and documents
Discovery and characterization of a potent Wnt and hedgehog signaling pathways dual inhibitor
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
, p. 110 - 121 (2018)
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.
FUSED GLYCOSIDASE INHIBITORS
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Page/Page column 121, (2020/09/08)
Compounds of formula (I), wherein A, Z, E, R1, R2, m and n have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.
BICYCLIC HYDROXAMIC ACIDS USEFUL AS INHIBITORS OF MAMMALIAN HISTONE DEACETYLASE ACTIVITY
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, (2017/07/14)
A compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. The compound is an inhibitor of a histone deacetylase, and as such is useful in terepy, e.g. in the treatment of autoimmune disorders, mental disorders, neurodegenerative disorders, and hyperproliferative disorders.
