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

Li Tan; Zhang Zhang; Donglin Gao; Jinfeng Luo; Zheng-Chao Tu; Zhengqiu Li; Lijie Peng; Xiaomei Ren; Ke Ding

doi:10.1021/acs.jmedchem.6b00608

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. Epub 2016 Jul 19.

Authors

Li Tan^{1

2}, Zhang Zhang^{1

3}, Donglin Gao^{1

2}, Jinfeng Luo¹, Zheng-Chao Tu¹, Zhengqiu Li³, Lijie Peng³, 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Axl Receptor Tyrosine Kinase
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Female
Humans
Male
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / pathology
Mice
Mice, Inbred BALB C
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / metabolism
Quinolines / chemical synthesis
Quinolines / chemistry
Quinolines / pharmacology*
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship
Wound Healing / drug effects
Xenograft Model Antitumor Assays

Substances

4-oxo-1,4-dihydroquinoline-3-carboxamide
Antineoplastic Agents
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Quinolines
Receptor Protein-Tyrosine Kinases
Axl Receptor Tyrosine Kinase