title: 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors.
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.
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|University of Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|University of Chinese Academy of Sciences , 19 Yuquan Road, Beijing 100049, China.
authors.forename: Donglin
authors.initials: D
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.
authors.forename: Zheng-Chao
authors.initials: ZC
authors.lastname: Tu
authors.affiliation: School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Zhengqiu
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Lijie
authors.initials: L
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , 190 Kaiyuan Avenue, Guangzhou 510530, China.|School of Pharmacy, Jinan University , 601 Huangpu Avenue West, Guangzhou 510632, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C000591437:4-oxo-1,4-dihydroquinoline-3-carboxamide; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase