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. Epub 2019 Jan 30.

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.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Axl Receptor Tyrosine Kinase
  • Cell Line, Tumor
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Quinolones / chemistry*
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*

Substances

  • Anti-Bacterial Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Quinolones
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase