Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors

[Display omitted] 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...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (11), p.2594-2599
Hauptverfasser: Fan, Jun, Dai, Yang, Shao, Jingwei, Peng, Xia, Wang, Chen, Cao, Sufen, Zhao, Bin, Ai, Jing, Geng, Meiyu, Duan, Wenhu
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Sprache:eng
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Zusammenfassung:[Display omitted] 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 compound 29 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 that 29 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.04.028