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4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-19 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00608 Li Tan 1, 2 , Zhang Zhang 1, 3 , Donglin Gao 1, 2 , Jinfeng Luo 1 , Zheng-Chao Tu 1 , Zhengqiu Li 3 , Lijie Peng 3 , Xiaomei Ren 1, 3 , Ke Ding 1, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-07-19 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00608 Li Tan 1, 2 , Zhang Zhang 1, 3 , Donglin Gao 1, 2 , Jinfeng Luo 1 , Zheng-Chao Tu 1 , Zhengqiu Li 3 , Lijie Peng 3 , Xiaomei Ren 1, 3 , Ke Ding 1, 3
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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 Kd 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:
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。
更新日期:2016-07-19
中文翻译:
![](https://scdn.x-mol.com/jcss/images/paperTranslation.png)
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。