Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors
Design, synthesis and biological evaluation of pyrazolylaminoquinazoline derivatives as highly potent pan-fibroblast growth factor receptor inhibitors
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吡唑氨基喹唑啉衍生物作为高效泛成纤维细胞生长因子受体抑制剂的设计、合成和生物学评价
DOI：
10.1016/j.bmcl.2016.04.028
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发表时间：
2016
影响因子：
2.7
通讯作者：
Duan Wenhu
中科院分区：
文献类型：
--
作者：
Fan Jun;Dai Yang;Shao Jingwei;Peng Xia;Wang Chen;Cao Sufen;Zhao Bin;Ai Jing;Geng Meiyu;Duan Wenhu
成纤维细胞生长因子受体(FGFRs)是重要的肿瘤学靶点，因为这一信号通路在多种人类癌症中调节失调。我们鉴定了一系列吡唑氨基喹唑啉衍生物是一种有效的低纳摩尔效价的FGFR抑制剂。具有代表性的化合物29强烈抑制FGFR依赖的癌细胞中FGFR1-3的活性，抑制FGFR信号转导；无论FGFR激活机制的复杂性如何，FGFRs驱动的细胞增殖也被强烈抑制，这进一步证实了29是一个有效的泛FGFR抑制剂。我们的结构的灵活性提供了保持与突变的FGFR的良好亲和力的可能性，这对于开发具有长期疗效的TKI是重要的。
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 compound29strongly 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 that29was 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.