Molecular Mechanisms of Quizartinib Resistance in FLT3 Mutants

D835Y and F691L FLT3 kinase-domain mutations confer quizartinib resistance in FLT3-ITD-positive AML by destabilizing the inactive DFG-out state, with binding free-energy drops of 5 and 10 kcal/mol versus wild-type.

• Why it matters: Acquired resistance limits quizartinib in FLT3-ITD-positive acute myeloid leukemia, occurring in up to 40% of patients with progression, but the structural mechanisms for key mutations are unclear.
• What they did: Triplicate 200-ns all-atom molecular dynamics simulations combined conformational analysis, MM-GBSA binding free-energy calculations, and binding-pocket characterization for wild-type FLT3, FLT3-D835Y, and FLT3-F691L with quizartinib.
• The result: D835Y disrupts the activation-loop electrostatic network and lowers Cys694 hydrogen-bond occupancy from 85% to 45%, while F691L abolishes van der Waals contacts and opens a 120 cubic Angstrom hydrophobic void; Ba/F3 CCK-8 and p-FLT3 (Y591) Western blots corroborate the resistance hierarchy (F691L > D835Y > WT).

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