4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors

  • J Med Chem. 2016 Jul 28;59(14):6807-25. 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
Affiliations
  • 1. State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
  • 2. University of Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
  • 3. School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
PMID: 27379978 DOI: 10.1021/acs.jmedchem.6b00608
Abstract

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.

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