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. (1st January 2020)

• Record Type: Journal Article
• Authors: Liu, Jian; Wen, Yu; Gao, Lina; Gao, Liang; He, Fengjun; Zhou, Jingxian; Wang, Junwei; Dai, Rupeng; Chen, Xiaojing; Kang, Di; Hu, Lihong
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 72
• Page End: 84
• Publication Date: 2020-01-01
• Subjects: Anticancer -- FGFR1 -- FGFR1 inhibitor -- Fragment-based virtual screening; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2019.1673745
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1 H -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. Graphical Abstract: UF0001