期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 14, 页码 6807-6825出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00608
关键词
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资金
- National Natural Science Foundation of China [81425021, 21572230]
- Guangzhou Science Technology and Innovation Commission [201508030036]
- Natural Science Foundation of Guangdong Province [2015A030312014]
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-beta 1-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.
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