FLT3 inhibitors in AML: from classic scaffolds to next-generation approaches

FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML); mutations within FLT3, specifically ITD lesions and TKD point mutations, promote proliferation and are associated with poor prognosis. Although FLT3 inhibition is central to AML therapy, resistance, particularly via D835 activation-loop variants and the F691L gatekeeper substitution, limits durability. Among the major therapeutic classes, type I inhibitors bind the active (DFG-in) conformation, whereas type II inhibitors stabilize the inactive (DFG-out) state. In contrast, irreversible covalent inhibitors target reactive cysteine residues within the kinase domain. Collectively, these approaches represent complementary therapeutic strategies with distinct resistance liabilities and structural design considerations. This review integrates structural biology with medicinal-chemistry evidence across type I, type II, irreversible, and dual-modality FLT3 inhibitors, analyzing how hinge contacts, back-pocket occupancy, and warhead placement govern activity across wild-type and mutant FLT3. We map resistance-defining residues (e.g. F691, D835, N676, N701) and design tactics to preserve potency against resistant variants. We also summarize combination therapy that augments selective FLT3 blockade and outline PROTAC approaches that induce FLT3 degradation, positioning these modalities as alternatives when single-molecule polypharmacology is constrained. Finally, we catalogue dual-target FLT3 chemotypes, highlighting examples that retain activity against F691L and D835 in cellular systems and xenografts. Overall, this review provides a section-by-section guide covering FLT3 structure and mutation hotspots, analyses of type I, type II, and irreversible inhibitors, dual-modality designs, combinations, PROTACs, and future perspectives. It links binding mode, covalent engagement, and second-target selection to recurrent resistance biology to guide more resilient FLT3-targeted therapies for high-risk AML.