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

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.