Structure-based identification of potent fibroblast growth factor receptor 4 (FGFR4) inhibitors as potential therapeutics for hepatocellular carcinoma

Fibroblast growth factor receptor 4 (FGFR4), a member of the fibroblast growth factor receptor family, plays a crucial role in cell growth, differentiation, and tissue repair. Increased FGFR4 expression has been detected in various cancers, including lung, liver, kidney and pancreatic cancer, making it a potential drug target. In this study, we conducted a structure-based virtual screening campaign to identify potential FGFR4 inhibitors. The retained compounds were further filtered based on pan assay interference compounds (PAINS) and absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, leading to the identification of two promising candidates: MFCD00832235 and MFCD00204244. Quantum mechanical (QM) calculations revealed a large Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO) (HUMO-LUMO) gaps for both compounds, indicating high dynamic stability and low chemical reactivity. Moreover, the stability of MFCD00832235 and MFCD00204244 at the adenosine triphosphate (ATP)-binding site of FGFR4 was confirmed through molecular dynamics (MD) simulations. The molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) approach predicted favorable binding free energy values for both compounds with the target protein. <i>In vitro</i> assay revealed that MFCD00832235 and MFCD00204244 inhibited the growth of HepG2 cells with IC₅₀ values of 47.42 ± 12.93 µM and 77.83 ± 19.17 µM, respectively. Overall, this study suggested that MFCD00832235 and MFCD00204244 were potential FGFR4 inhibitors and may serve as start points for developing novel modulators of FGFR4 for cancer treatment, particularly hepatocellular carcinoma.