Targeting FLT3 in Acute Myeloid Leukemia: Structural Insights and Key Challenges

Mutations in FLT3 (FMS-like tyrosine kinase 3) are directly related to the development of acute myeloid leukemia (AML), contributing to the dysregulated proliferation and survival of malignant myeloid cells. FLT3 inhibitors (FLT3i), such as gilteritinib and quizartinib, have demonstrated relevant clinical benefits, including symptom relief and increased overall survival in patients with AML. However, the duration of response to FLT3i remains limited due to the emergence of resistance. In this scenario, the development of targeted therapies has emerged as a promising strategy to overcome these limitations, aiming to address the restrictions observed in the previous generation. These approaches range from the combination of FLT3i with other antileukemic agents to the use of multitarget inhibitors capable of simultaneously modulating FLT3 and other relevant molecular targets, as well as the development of next-generation inhibitors that are more selective and capable of maintaining activity against secondary mutations, such as the gatekeeper mutation (F691L), which confers resistance to clinically available drugs. This review article addresses the therapeutic relevance of FLT3i in AML and provides an overview of the binding modes of representative FLT3 inhibitors. Structural and conformational aspects involved in the interaction with this target, with emphasis on the ATP-binding site, as well as the impact of resistance-associated mutations, are discussed. In addition, this work seeks to correlate the binding modes described in the literature with experimental activity data.