2. Academic Validation
  3. Quinolone antibiotic derivatives as new selective Axl kinase inhibitors

Quinolone antibiotic derivatives as new selective Axl kinase inhibitors

  • Eur J Med Chem. 2019 Mar 15;166:318-327. doi: 10.1016/j.ejmech.2019.01.065.
Li Tan 1,  Zhang Zhang 2,  Donglin Gao 3,  Shingpan Chan 1,  Jinfeng Luo 3,  Zheng-Chao Tu 3,  Zhi-Min Zhang 1,  Ke Ding 4,  Xiaomei Ren 5,  Xiaoyun Lu 6
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China and Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
  • 2 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China and Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou, 510530, China.
  • 3 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou, 510530, China.
  • 4 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China and Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: dingke@jnu.edu.cn.
  • 5 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China and Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: ren_xiaomei@jnu.edu.cn.
  • 6 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MOE) of People's Republic of China and Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: luxy2016@jnu.edu.cn.
PMID: 30731400 DOI: 10.1016/j.ejmech.2019.01.065
Abstract

Axl is a new promising molecular target for antineoplastic therapies. A series of quinolone Antibiotic derivatives were designed and synthesized as new selective Axl inhibitors. One of the most promising compound 8i bound tightly to Axl with a Kd value of 1.1 nM, and inhibited its kinase activity with an IC50 value of 26 nM. The compound also significantly inhibited the phosphorylation of Axl and dose dependently inhibited cell invasion and migration in TGF-β1 induced MDA-MD-231 breast Cancer cells. In addition, 8i demonstrated reasonable pharmacokinetic properties and exhibited extraordinary target selectivity over 468 kinases except for FLT3 (IC50 = 50 nM)), with a S(10) and S(35) value of 0.022 and 0.42 at 1.0 μM, respectively. Compound 8i may serve as a new valuable lead compound for future Anticancer drug discovery.

Keywords

Axl; Breast cancer; Quinolones; Selective inhibitor.

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