Fibroblast growth factor receptor (FGFR) is an attractive target for cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, showed the most potent effect on enzyme activity inhibition and anti-proliferative activity against the tested cancer cell lines. Significantly, could inhibit the enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote cancer cell apoptosis and inhibit cancer cell invasion and metastasis. Moreover, had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.

中文翻译：

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发现 N-(4-((6-(3,5-二甲氧基苯基)-9H-嘌呤衍生物）作为不可逆共价 FGFR 抑制剂

成纤维细胞生长因子受体（FGFR）是癌症治疗的一个有吸引力的靶点，但现有的FGFR抑制剂似乎很难满足临床应用的需求。在此，通过选择几个五元和六元氮杂环作为母体支架，用不同的取代基来接管FGFR蛋白活性口袋中的疏水区域，设计并合成了许多不可逆共价FGFR抑制剂。在所得的目标化合物中，对测试的癌细胞系的酶活性抑制和抗增殖活性表现出最有效的作用。值得注意的是，可以通过与 FGFR1 和 FGFR4 蛋白实现不可逆共价结合来抑制酶活性。它还可以调节FGFR介导的信号通路和线粒体凋亡通路，促进癌细胞凋亡，抑制癌细胞侵袭和转移。此外，具有良好的代谢稳定性，并在MDA-MB-231异种移植肿瘤小鼠模型中表现出较强的抗肿瘤活性。