Quinolone antibiotic derivatives as new selective Axl kinase inhibitors

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. Compound 8i bound to Axl with a Kd value of 1.1 nM, and inhibited its kinase activity with an IC50 value of 26 nM. Further, 8i exhibited extraordinary target selectivity over 468 kinases, with a S(10) and S(35) value of 0.022 and 0.42 at 1.0 μM, and significantly inhibited the phosphorylation of Axl and dose dependently inhibited cell invasion and migration in TGF-β1 induced MDA-MD-231 breast cancer cells. [Display omitted] •Quinolone 8i bound tightly to Axl with a Kd value of 1.1 nM.•8i dose dependently inhibited cell invasion and migration in TGF-β1 induced breast cancer cells.•8i exhibited extraordinary target selectivity over 468 kinases with a S(10) value of 0.022 at 1.0 μM.