SGI-7079 as a novel type I FLT3 inhibitor overcomes resistance to gilteritinib and quizartinib mediated by ITD and TKD mutations in acute myeloid leukemia

FLT3-ITD mutations are among the most frequent mutations in acute myeloid leukemia (AML) and are associated with poor prognosis and high relapse rates. Despite the extensive use of existing FLT3 inhibitors, resistance caused by secondary TKD mutations remains a major challenge. Therefore, the development of next-generation FLT3 inhibitors with broad-spectrum activity and sensitivity to drug-resistant mutations is of considerable clinical value. In this study, we systematically evaluated the antileukemic activity of a novel type I FLT3 inhibitor, SGI-7079, within the context of FLT3-ITD mutations and drug-resistant secondary mutations. SGI-7079 notably inhibited the proliferation of AML cell lines harboring FLT3-ITD mutations and multiple drug-resistant secondary mutations, such as D835Y/V/F, Y842C, and F691L, in vitro. Mechanistically, SGI-7079 was bound stably to the FLT3 protein, as indicated by molecular docking and CETSA analyses; inhibited FLT3 phosphorylation and downstream STAT5, AKT, and ERK signaling; and induced G1-phase arrest and apoptosis. In mouse models harboring FLT3-ITD mutations, SGI-7079 greatly reduced leukemia burdens, mitigated histopathological abnormalities, and prolonged median survival. Notably, SGI-7079 effectively overcame gilteritinib resistance driven by FLT3-ITD-F691L mutations in vivo and exhibited effectiveness against quizartinib-resistant FLT3-ITD-D835Y mutations. Importantly, SGI-7079 demonstrated notable inhibitory activity in primary AML cells from FLT3-ITD-positive patients, with effectiveness surpassing that of approved agents gilteritinib and quizartinib. In summary, this study is the first to demonstrate that SGI-7079 provides broad-spectrum and potent inhibitory activity across diverse FLT3 mutation contexts, showing remarkable advantages against drug-resistant mutations, especially F691L, and exhibits high potential for clinical translation.