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Article 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, . This compound exhibited potent inhibitory activity against FGFR1 V561M with an IC 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 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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12358978 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.5c00205 | DOI Listing |
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