Axl is a new potential target for anticancer drug discovery. A series of 4-oxo-1,4-dihydroquinoline-3-carboxamides were designed and synthesized as highly potent Axl kinase inhibitors. One of the most promising compounds, 9im, tightly bound with Axl protein and potently inhibited its kinase function with a K_d value of 2.7 nM and an IC₅₀ value of 4.0 nM, respectively, while was obviously less potent against most of the 403 wild-type kinases evaluated at a relatively high concentration. The compound dose-dependently inhibited the TGF-β1-induced epithelial–mesenchymal transition (EMT) and suppressed the migration and invasion of MDA-MB-231 breast cancer cells. In addition, 9im also demonstrated reasonable pharmacokinetics properties in rats and exhibited in vivo therapeutic effect on hepatic metastasis in a xenograft model of highly metastatic 4T1 murine breast cancer cells. Compound 9im may serve as a lead compound for new anticancer drug discovery and a valuable research probe for further biological investigation on Axl.

中文翻译：

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4-Oxo-1,4-dihydroquinoline-3-carboxamide衍生物作为新的Axl激酶抑制剂

Axl是抗癌药物发现的新潜在靶标。设计并合成了一系列4-oxo-1,4-dihydroquinoline-3-carboxamides作为高效的Axl激酶抑制剂。最有前途的化合物之一9im与Axl蛋白紧密结合，并有效抑制其激酶功能，K _d值为2.7 nM，IC ₅₀值为4.0 nM，而对大多数403种野生动物的效价明显较低相对高浓度评估的三型激酶。该化合物可剂量依赖性地抑制TGF-β1诱导的上皮-间质转化（EMT），并抑制MDA-MB-231乳腺癌细胞的迁移和侵袭。另外，9im在高转移性4T1鼠乳腺癌细胞的异种移植模型中，他还证明了其在大鼠中的合理药代动力学特性，并显示了对肝转移的体内治疗作用。化合物9im可用作新的抗癌药物发现的先导化合物，以及对Axl进行进一步生物学研究的有价值的研究探针。