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The kinase FLT3 internal tandem duplication(FLT3-ITD)is related to poor clinical outcomes of acute myeloid leukemia(AML).FLT3 inhibitors have provided novel strategies for the treatment of FLT3-ITD-positive AML.But they are limited by rapid development of acquired resistance and refractory in monotherapy.Recent evidence shows that inducing the degradation of FLT3-mutated protein is an attractive strategy for the treatment of FLT3-ITD-positive AML,especially those with FLT3 inhibitor resistance.In this study we identified Wu-5 as a novel USP10 inhibitor inducing the degradation of FLT3-mutated protein.We showed that Wu-5 selectively inhibited the viability of FLT3 inhibitor-sensitive(MV4-11,Molm13)and-resistant(MV4-11R)FLT3-ITD-positive AML cells with IC50of 3.794,5.056,and 8.386 μM,respectively.Wu-5(1-10 μM)dose-dependently induced apoptosis of MV4-11,Molm13,and MV4-11R cells through the proteasome-mediated degradation of FLT3-ITD.We further demonstrated that Wu-5 directly interacted with and inactivated USP10,the deubiquitinase for FLT3-ITD in vitro(IC50 value=8.3 μM)and in FLT3-ITD-positive AML cells.Overexpression of USP10 abrogated Wu-5-induced FLT3-ITD degradation and cell death.Also,the combined treatment of Wu-5 and crenolanib produced synergistic cell death in FLT3-ITD-positive cells via the reduction of both FLT3 and AMPKα proteins.In support of this,AMPKα inhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib,while AMPKα activator metformin inhibited the anti-leukemia effect of crenolanib.In summary,we demonstrate that Wu-5,a novel USP10 inhibitor,can overcome FLT3 inhibitor resistance and synergistically enhance the anti-AML effect of crenolanib through targeting FLT3 and AMPKα pathway.