Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors. Issue 11 (1st June 2016)

• Record Type: Journal Article
• Authors: Fan, Jun; Dai, Yang; Shao, Jingwei; Peng, Xia; Wang, Chen; Cao, Sufen; Zhao, Bin; Ai, Jing; Geng, Meiyu; Duan, Wenhu
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 11(2016)
• Page Start: 2594
• Page End: 2599
• Publication Date: 2016-06-01
• Subjects: Antitumor -- FGFR inhibitor -- Pyrazolylaminoquinazoline; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Fibroblast growth factor receptors (FGFRs) are important oncology targets due to the dysregulation of this signaling pathway in a wide variety of human cancers. We identified a series of pyrazolylaminoquinazoline derivatives as potent FGFR inhibitors with low nanomolar potency. The representative compound29 strongly inhibited FGFR1–3 kinase activity and suppressed FGFR signaling transduction in FGFR-addicted cancer cells; FGFRs-driven cell proliferation was also strongly inhibited regardless of mechanistic complexity implicated in FGFR activation, which further confirmed that29 was a potent pan-FGFR inhibitor. The flexibility of our structure offered the potential to preserve good affinity for mutant FGFR, which is important for developing TKIs with long-term efficacy.