Abstract
The FGFR1 V561M mutation significantly reduces the efficacy of current FGFR1 inhibitors, creating an urgent need for targeted second-generation therapies. In this study, we developed a comprehensive virtual screening protocol that combines energy-based screening and machine learning techniques, leading to the identification of a novel compound, 1457983-28-6. This compound exhibited potent inhibitory activity against FGFR1 V561M with an IC(50) of 90.24 nM in homogeneous time-resolved fluorescence (HTRF) bioassays. Additionally, it demonstrated significant growth inhibition in the Huh-7 cell line and effectively suppressed clonal formation. Molecular dynamics simulations revealed critical binding interactions between 1457983-28-6 and both FGFR1 wild-type and V561M variants, with Lys514 playing a pivotal role. Targeting this residue may provide promising strategies to overcome resistance associated with the V561M mutation in FGFR1 inhibitors.