Quinacrine binds to the kinase domain of FGFR1 and inhibits its activity

Abstract

BackgroundFGF family receptors, especially FGFR1, have been widely implicated for their potential role in the promotion of oncogenesis and chemoresistance in lung cancer. Quinacrine, an anti-malarial drug, has been widely reported to exhibit anti-neoplastic properties through the activation of p53 and simultaneous inhibition of NF-kB signaling pathways in cancer cells. MethodsThe binding of QC to FGFR1 was studied using molecular docking and molecular dynamics simulation studies. The experimental kinase activity assay for the protein was performed using a luminescence-based kinase assay. FGF-induced phosphorylation and proliferation were studied by cell counting and western blotting. Matrigel-based cell migration was conducted to assess migration activity. ResultsQC interacted with multiple residues around the kinase insert domain of FGFR1 through hydrogen bonding, hydrophobic interactions, and water bridges. The kinase activity inhibition assay demonstrated a significant reduction in FGFR1 kinase activity by QC at higher concentrations, which was further observed at the cellular level in inhibition of FGFR1 phosphorylation and proliferation by QC at higher exposure concentrations of FGF stimulated cells. These effects were further validated downstream in the FGF-induced activation of cell migration. ConclusionQC did form a stable interaction with residues of FGFR1 at another allosteric site surrounding the kinase domain, leading to inhibition of its kinase activity at higher drug concentrations. This effect was further observed at the cellular level in both acidic and basic FGF ligand-induced proliferation, phosphorylation of FGFR1, and cell migration, where a trend of significant reduction in activity was observed at higher drug concentrations.