Design, synthesis, and antiproliferative activity assessment of non-ATP-competitive fibroblast growth factor receptor 1 inhibitors

Fibroblast growth factor receptor 1 (FGFR1) is considered a therapeutic target for multiple cancers, including gastric cancer. FGFR1 inhibitors, being ATP competitors, can prevent the kinase domain and the downstream signaling cascade from phosphorylation and thus have the potential to treat cancers associated with aberrant FGFR1 activation. However, untargeted inhibition may cause numerous side effects. Thus, a non-ATP competitive FGFR1 inhibitor should be urgently identified and explored. In this study, we designed and synthesized 17 derivatives of nordihydroguaiaretic acid (NDGA), a known ATP-independent FGFR3 inhibitor. In the kinase activity assay, 3,5-bis(2-fluorobenzylidene)piperidin-4-one (1B) showed the highest kinase inhibitory activity among all derivatives and was thus identified as a non-ATP-competitive FGFR1 inhibitor. In the biological effect evaluation, 1B restrained the FGFR−FRS2−ERK signaling pathway in a dose-dependent manner and inhibited the growth of two gastric cancer cell lines. Overall, 1B can be considered as a potential candidate for treating gastric cancer and as an outstanding lead compound for the discovery of novel non-ATPcompetitive FGFR1 inhibitors.