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A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression

文献类型：期刊论文

作者Wang, Yingcong1; Huang, Jing2; Li, Bo3,4; Xue, Han2; Tricot, Guido5; Hu, Liangning1; Xu, Zhijian3,4; Sun, Xiaoxiang6; Chang, Shuaikang1; Gao, Lu1
刊名CANCER RESEARCH
出版日期2020-02-01
卷号80期号:3页码:536-548
ISSN号0008-5472
DOI10.1158/0008-5472.CAN-18-3987
通讯作者Shi, Jumei(shijumei@tongji.edu.cn)
英文摘要The AAA- ATPase TRIP13 drives multiple myeloma progression. Here, we present the crystal structure of wild-type human TRIP13 at a resolution of 2.6 A. A small-molecule inhibitor targeting TRIP13 was identified on the basis of the crystal structure. The inhibitor, designated DCZ0415, was confirmed to bind TRIP13 using pull-down, nuclear magnetic resonance spectroscopy, and surface plasmon resonance-binding assays. DCZ0415 induced antimyeloma activity in vitro, in vivo, and in primary cells derived from drug-resistant patients with myeloma. The inhibitor impaired nonhomologous end joining repair and inhibited NF-kB activity. Moreover, combining DCZ0415 with the multiple myeloma chemotherapeutic melphalan or the HDAC inhibitor panobinostat induced synergistic antimyeloma activity. Therefore, targeting TRIP13 may be an effective therapeutic strategy for multiple myeloma, particularly refractory or relapsed multiple myeloma. Significance: These findings identify TRIP13 as a potentially new therapeutic target in multiple myeloma.
WOS关键词BREAK REPAIR ; BONE-MARROW ; CHECKPOINT ; EXPRESSION ; TUMOR ; RECOMBINATION ; THERAPY ; MODEL
资助项目National Natural Science Foundation of China[81870158] ; National Natural Science Foundation of China[81570190] ; National Natural Science Foundation of China[31570766] ; National Natural Science Foundation of China[U1632130] ; National Natural Science Foundation of China[81602515] ; National Natural Science Foundation of China[81529001] ; National Natural Science Foundation of China[81670194] ; National Key R&D Program of China[2016YFA0501803] ; National Key R&D Program of China[2017YFA0504504] ; National Key R&D Program of China[2016YFA0502301] ; Chinese Pharmaceutical Association - Yiling Biopharmaceutical Innovation Project[CPAYLJ201908]
WOS研究方向Oncology
语种英语
出版者AMER ASSOC CANCER RESEARCH
WOS记录号WOS:000514161100017
源URL[http://119.78.100.183/handle/2S10ELR8/281317]  
专题中国科学院上海药物研究所
通讯作者Shi, Jumei
作者单位1.Tongji Univ, Sch Med, Dept Hematol, Shanghai Peoples Hosp 10, Shanghai, Peoples R China
2.Shanghai Jiao Tong Univ, Peoples Hosp 9, Shanghai Inst Precis Med, Sch Med, Shanghai, Peoples R China
3.Chinese Acad Sci, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Shanghai, Peoples R China
5.Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA
6.Tongji Univ, Clin & Translat Res Ctr, Shanghai Matern & Infant Hosp 1, Shanghai Key Lab Signaling & Dis Res,Sch Life Sci, Shanghai, Peoples R China
7.Tongji Univ, Canc Ctr, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yingcong,Huang, Jing,Li, Bo,et al. A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression[J]. CANCER RESEARCH,2020,80(3):536-548.
APA Wang, Yingcong.,Huang, Jing.,Li, Bo.,Xue, Han.,Tricot, Guido.,...&Shi, Jumei.(2020).A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression.CANCER RESEARCH,80(3),536-548.
MLA Wang, Yingcong,et al."A Small-Molecule Inhibitor Targeting TRIP13 Suppresses Multiple Myeloma Progression".CANCER RESEARCH 80.3(2020):536-548.

入库方式： OAI收割

来源：上海药物研究所

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