Medicinal Insights Into FLT3 Inhibitors as Anticancer Agents: Current Status and Future Direction

Abstract

FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) important for hematopoietic stem cell proliferation, differentiation, and survival. Ligand-induced dimerization activates the downstream pathways such as RAS/MAPK, PI3K/AKT, and STAT5. Mutations such as internal tandem duplications (ITD) and tyrosine kinase domain (TKD) cause constitutive activation, poor prognosis, and driving leukemogenesis in acute myeloid leukemia (AML). Over the past 5 years, FLT3-targeted therapy has advanced significantly. Second-generation FLT3 inhibitors such as gilteritinib and quizartinib displayed improved selectivity and durable efficacy. Quizartinib was approved in 2023 for FLT3-ITD–positive AML alongside intensive chemotherapy. Clinical trials have explored some compounds such as crenolanib, momelotinib, and various novel molecules in combination regimens, which are enhancing remission rates. This review comprehensively compiles diverse chemical scaffolds investigated as FLT3 inhibitors such as pyrimidine, benzimidazole, imidazole, indole, isoxazole, quinazoline, and so on. Structure–activity relationship (SAR) analyses and molecular docking studies are briefly discussed along with highlighting potency against FLT3-ITD and resistant FLT3-TKD mutants. Despite therapeutic gains, resistance through secondary mutations or compensatory pathway activation remains a challenge. Future directions should focus on structure-guided design, rational combination therapies, and expanding applications to other FLT3-altered malignancies. This review integrates updated FLT3 biology, clinical outcomes, medicinal chemistry, and computational insights to support personalized FLT3-targeted treatment strategies.