Design, Synthesis, and Biological Activities Evaluation of Type I FLT3 Inhibitors for the Treatment of Acute Myeloid Leukemia

The abnormal overexpression of FLT3 kinase is intimately associated with pathogenesis of acute myeloid leukemia (AML), positioning FLT3 inhibitors as pivotal therapeutic agents. Despite the availability of three FDA-approved FLT3 inhibitors, their clinical utility is hampered by resistance stemming from tyrosine kinase domain (TKD) mutations. Through an integrative analysis of case studies, we identified a potential advantage of type I FLT3 inhibitors in overcoming TKD mutation-induced resistance. Structure-activity relationships (SAR) analysis indicated that FW-1 exhibited over 50% inhibition against FLT3 at a concentration of 1 mu M and demonstrated potent activity against AML cell lines MV4-11 (IC50 = 2.68 mu M) and MOLM-13 (IC50 = 1.03 mu M). In our cellular mechanistic studies, FW-1 also effectively induced apoptosis by arresting cell cycle progression in the G0/G1 phase. This study introduces FW-1 as a promising lead for type I FLT3 inhibitor, warranting further optimization.