Rational design of next-generation FLT3 inhibitors in acute myeloid leukemia: From laboratory to clinics

Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are among the most common genetic alterations in acute myeloid leukemia (AML), affecting approximately 30 % of patients and leading to a poor prognosis. The development of FLT3-targeted inhibitors has achieved significant progress. First-generation multi-kinase inhibitors like midostaurin and second-generation agents such as gilteritinib and quizartinib have shown success. However, drug resistance, often due to D835Y and F691L gatekeeper mutations, remains a major challenge. In response, a new generation of FLT3 inhibitors (FLT3i) have been designed to simultaneously target both FLT3 internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations. This review examines the mechanisms of FLT3 in the regulation of AML and examines preclinical research on novel FLT3i over the past five years. It discusses how these agents, including small-molecule like STI-8591, compounds 36 and 80 and novel therapeutic strategies such as CLN-049, and SENTI-202, are designed to combat resistance. The goal is to provide a medicinal chemistry perspective to provide insights for the design of novel small-molecule FLT3i.