血管内皮生长因子受体（VEGFR）是一种受体酪氨酸激酶，被认为是异常血管生成疾病的新兴靶点。在这项研究中，使用基于多靶点激酶抑制剂ponatinib的支架跳跃策略设计并合成了作为VEGFR选择性抑制剂的新型萘咪唑并[1,2-b]哒嗪杂化物。在评估的化合物中，衍生物 9k (WS-011) 对 VEGFR-2 表现出最有效的抑制效力 (IC50= 8.4nM)，并且与 ponatinib 相比，对一组 70 种激酶表现出优异的 VEGFR 选择性。此外，9k对多种癌细胞系，尤其是结肠癌HT-29细胞具有良好的细胞毒作用，并具有可接受的口服生物利用度。此外，9k显着抑制人脐静脉内皮细胞（HUVEC）细胞的迁移和侵袭，并通过上调HT-29细胞中的凋亡蛋白诱导细胞凋亡。 9k还有效抑制VEGFR-2信号通路的激活，进而抑制HT-29细胞的生长和体外HUVEC的管形成。所有研究结果都表明，9k 可以被认为是一种有前途的抗血管生成先导化合物，值得进一步研究。© 2024 Deutsche Pharmazeutische Gesellschaft。

The vascular endothelial growth factor receptor (VEGFR) is a receptor tyrosine kinase that is regarded as an emerging target for abnormal angiogenesis diseases. In this study, novel naphthalene imidazo[1,2-b]pyridazine hybrids as VEGFR selective inhibitors were designed and synthesized using a scaffold hopping strategy based on ponatinib, a multitarget kinase inhibitor. Among the evaluated compounds, derivative 9k (WS-011) demonstrated the most potent inhibitory potency against VEGFR-2 (IC50 = 8.4 nM) and displayed superior VEGFR selectivity over a panel of 70 kinases compared with ponatinib. Furthermore, 9k possessed good cytotoxic effects on various cancer cell lines, especially the colon cancer HT-29 cells, with an acceptable oral bioavailability. Moreover, 9k significantly inhibited the migration and invasion of human umbilical vein endothelial cells (HUVEC) cells and induced apoptosis through the upregulation of apoptotic proteins in HT-29 cells. 9k also effectively suppressed the activation of VEGFR-2 signaling pathways, which in turn inhibited the growth of HT-29 cells and the tube formation of HUVECs in vitro. All of the findings revealed that 9k could be considered a promising antiangiogenesis lead that merits further investigation.© 2024 Deutsche Pharmazeutische Gesellschaft.