Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 35, Issue 1, Pages 72-84Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2019.1673745
Keywords
Anticancer; FGFR1; FGFR1 inhibitor; Fragment-based virtual screening
Funding
- National Natural Science Foundation of China [81703342, 81473110, 81773596]
- Natural Science Foundation of Jiangsu Higher Education Institutions [17KJA360004, 16KJB350003]
- Natural Science Foundation of Jiangsu [BK2016105]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [SJCX18_0448, KYCX18_1614]
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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.
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