Wu-5, a novel USP10 inhibitor, enhances crenolanib-induced FLT3-ITD-positive AML cell death via inhibiting FLT3 and AMPK pathways  

作　　者：Miao Yu Zhi-xiao Fang Wei-wei Wang Ying Zhang Zhi-lei Bu Meng Liu Xin-hua Xiao Zi-lu Zhang Xing-ming Zhang Yang Cao Ying-ying Wang Hu Lei Han-zhang Xu Yun-zhao Wu Wei Liu Ying-li Wu 

机构地区：[1]Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China [2]Hongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic MedicineChemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [3]Department of Hematology,Shanghai Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [4]Department of Transfusion Medicine,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [5]Department of Hematology,The Third Affiliated Hospital of Soochow University,The First People’s Hospital of Changzhou,Changzhou 213003,China

出　　处：《Acta Pharmacologica Sinica》2021年第4期604-612,共9页中国药理学报（英文版）

基　　金：supported in part by grants from the National Key Research and Development Program of China(No.2017YFA0505202);the National Basic Research Program of China(973 Program)(No.2015CB910403);the National Natural Science Foundation of China(Nos.81570118,81700475,81570112,81670139,and 21602133);the National Natural Science Foundation Youths of China(No.81700157);Innovative research team of high-level local universities in Shanghai(SSMU-ZDCX20181202).

摘　　要：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 IC50 of 3.794,5.056,and 8.386μM,respectively.Wu-5(1−10μM)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=8.3μM)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 AMPKαproteins.In support of this,AMPKαinhibitor compound C synergistically enhanced the anti-leukemia effect of crenolanib,while AMPKαactivator 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 AMPKαpathway.

关 键 词：AML Wu-5 crenolanib USP10 FLT3-ITD AMPKα Compound C METFORMIN 

分 类 号：R96[医药卫生—药理学]