Finding Novel Inhibitors of FMS-like Tyrosine Kinase 3 from Selected FDA-approved Anticancer Drugs: Insights from Molecular Docking, MD Simulations, and ADMET Profiling.

BACKGROUND

Wild-type FLT3 (WT-FLT3) has emerged as a relevant molecular target in Acute Myeloid Leukemia (AML), with increasing evidence implicating its role in leukemic proliferation and resistance, even in the absence of FLT3 mutations. Although gilteritinib is an approved FLT3 inhibitor, its efficacy in WT-FLT3 AML remains limited, underscoring the need for alternative strategies.

METHOD: We filtered 1,737 FDA-approved anticancer agents from the Selleckchem database using computational techniques to identify possible WT-FLT3 inhibitors. A total of 118 druglike compounds were docked against the WT-FLT3 binding site as determined by gilteritinib using AutoDock Vina; ADMET screening and MD simulations of 150 ns were executed on hit compounds using the ADMETSar server and GROMACS software, respectively.

RESULTS

In the end, 56 compounds with binding energies between -8.0 and -10.3 kcal/- mol were obtained, while the control, gilteritinib, returned -6.4 kcal/mol. Among this subset, Amlexanox (-9.5), sanguinarine (-10.3), crizotinib (-9.7), (S)-crizotinib (-9.7), and rutaecarpine (-10.0) showed high predicted affinity. Predictions from ADMET and 150 ns MD simulations indicated that amlexanox had stable, specific interactions with the WT-FLT3 active site, superior ADMET, and a concentrated free-energy basin with increased conformational stability. In contrast, sanguinarine and others raised significant toxicity risks.

CONCLUSION

These results suggest amlexanox is a potential new repurposing agent as a WT-FLT3 inhibitor in AML. This potential outcome needs urgent experimental confirmation through in vitro and in vivo models.