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 extensive use of FLT3 inhibitors, resistance caused by secondary TKD mutations remains a major challenge. Therefore, developing next-generation FLT3 inhibitors with broad-spectrum activity against drug-resistant mutations is of considerable clinical value. We systematically evaluated the antileukemic activity of a novel type I FLT3 inhibitor, SGI-7079, in the context of FLT3-ITD and secondary resistance mutations. SGI-7079 inhibited the proliferation of AML cell lines harboring FLT3-ITD and multiple resistant mutations, including D835Y/V/F, Y842C, and F691L, in vitro. Mechanistically, SGI-7079 bound stably to FLT3, inhibited FLT3 phosphorylation and downstream STAT5, AKT, and ERK signaling, and induced G1-phase arrest and apoptosis. In FLT3-ITD leukemia mouse models, including Ba/F3-FLT3-ITD and MOLM13 cell-derived xenografts, SGI-7079 reduced leukemia burden and splenic infiltration without significant toxicity. Notably, it overcame gilteritinib resistance in FLT3-ITD-F691L and quizartinib resistance in FLT3-ITD-D835Y in vivo. SGI-7079 also exhibited potent activity in primary AML cells from FLT3-ITD-positive patients, outperforming gilteritinib and quizartinib. These findings demonstrate that SGI-7079 provides broad-spectrum inhibition across diverse FLT3 mutation contexts, with distinct advantages against drug-resistant mutations, particularly F691L, highlighting its potential for clinical translation.