title: Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold.
abstract: Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy. Based on the structure of AZD4547 and NVPBGJ-398, we designed novel 1H-indazol-3-amine scaffold derivatives by utilizing scaffold hopping and molecular hybridization strategies. Consequently, twenty-eight new compounds were synthesized and evaluated for their inhibitory activity against FGFR1. Compound 7n bearing a 6-(3-methoxyphenyl)-1H-indazol-3-amine scaffold was first identified as a potent FGFR1 inhibitor, with good enzymatic inhibition (IC50 = 15.0 nM) and modest cellular inhibition (IC50 = 642.1 nM). The crystal structure of 7n bound to FGFR1 was obtained, which might provide a new basis for potent inhibitor design. Further structural optimization revealed that compound 7r stood out as the most potent FGFR1 inhibitor with the best enzyme inhibitory (IC50 = 2.9 nM) and cellular activity (IC50 = 40.5 nM).
authors.affiliation: School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. liyx417@fudan.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Xia
authors.initials: X
authors.lastname: Peng
authors.forename: Yang
authors.initials: Y
authors.lastname: Dai
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Sumei
authors.initials: S
authors.lastname: Ren
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Meiyu
authors.initials: M
authors.lastname: Geng
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Li
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D017468:Receptors, Fibroblast Growth Factor