Design, synthesis and biological evaluation of novel FGFR inhibitors bearing an indazole scaffold

• Published in: Organic & biomolecular chemistry 2015-07, Vol.13 (28), p.7643-7654
• Main Authors: Liu, Jian, Peng, Xia, Dai, Yang, Zhang, Wei, Ren, Sumei, Ai, Jing, Geng, Meiyu, Li, Yingxia
• Format: Article
• Language: English
• Subjects: Dose-Response Relationship, Drug; Drug Design; Humans; Indazoles - chemical synthesis; Indazoles - chemistry; Indazoles - pharmacology; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptors, Fibroblast Growth Factor - antagonists & inhibitors; Receptors, Fibroblast Growth Factor - metabolism; Structure-Activity Relationship
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob00778j

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).