- Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening
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Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.
- Liu, Jian,Wen, Yu,Gao, Lina,Gao, Liang,He, Fengjun,Zhou, Jingxian,Wang, Junwei,Dai, Rupeng,Chen, Xiaojing,Kang, Di,Hu, Lihong
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- Indazoles compound and its preparation and use (by machine translation)
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This invention belongs to the field of medicine synthesis, relates to novel indazoles, preparation method and application thereof, and containing said compounds as pharmaceutical composition of the active ingredient, and for preparing same as a medicament for the treatment of diseases related to tyrosine kinase FGFR, in particular of the FGFR associated the use of the medicament of cancer. Indazoles of this invention shown in a chemical formula represented by the following formula I, wherein the substituents are as defined in the specification; the compound by biological experimental results show that, for the fibroblast growth factor receptor (FGFR) has good inhibitory activity, can be used as a preparation for prevention and treatment of diseases associated with FGFR pharmaceutical, in particular for preparing and treating of FGFR-related cancer. (by machine translation)
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