Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound potently inhibited FGFR2 kinase activity with an IC of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

中文翻译：

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发现 LHQ490 作为一种高选择性成纤维细胞生长因子受体 2 (FGFR2) 抑制剂


成纤维细胞生长因子受体 2 (FGFR2) 是多种癌症的一个有吸引力的治疗靶点，但迄今为止还没有选择性 FGFR2 抑制剂被批准用于临床。在这里，我们报告了一系列新型选择性、不可逆 FGFR2 抑制剂的发现。代表性化合物可有效抑制 FGFR2 激酶活性，IC 值为 5.2 nM，并且对 FGFR1、FGFR3 和 FGFR4 的选择性分别为 >61 倍、>34 倍和 >293 倍。在一组 416 种激酶中也表现出高选择性。基于细胞的研究表明，它能有效抑制 BaF3-FGFR2 细胞的增殖，IC 值为 1.4 nM，并且对 BaF3-FGFR1 和亲代 BaF3 细胞分别显示 > 70 倍和 > 714 倍的选择性。更重要的是，有效抑制FGFR2信号通路，选择性抑制FGFR2驱动的癌细胞增殖，并诱导FGFR2驱动的癌细胞凋亡。总而言之，这项研究为进一步开发 FGFR2 靶向治疗药物提供了一种有效且高度选择性的 FGFR2 抑制剂。