The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway
文献类型：期刊论文
| 作者 | Wang, Yingcong3,6; Dong, Sanfeng1,4,5; Hu, Ke6; Xu, Li6; Feng, Qilin6; Li, Bo4,5; Wang, Guangli6; Chen, Gege6; Zhang, Bibo2; Jia, Xinyan6 |
| 刊名 | JOURNAL OF TRANSLATIONAL MEDICINE
 |
| 出版日期 | 2023-11-27 |
| 卷号 | 21期号:1页码:17 |
| 关键词 | Norcantharidin Derivative DCZ5417 TRIP13 Anti-myeloma MAPK |
| DOI | 10.1186/s12967-023-04739-7 |
| 通讯作者 | Zhu, Weiliang(wlzhu@simm.ac.cn) ; Shi, Jumei(shijumei@tongji.edu.cn) |
| 英文摘要 | BackgroundMultiple myeloma (MM), an incurable disease owing to drug resistance, requires safe and effective therapies. Norcantharidin (NCTD), an active ingredient in traditional Chinese medicines, possesses activity against different cancers. However, its toxicity and narrow treatment window limit its clinical application. In this study, we synthesized a series of derivatives of NCTD to address this. Among these compounds, DCZ5417 demonstrated the greatest anti-MM effect and fewest side effects. Its anti-myeloma effects and the mechanism were further tested.MethodsMolecular docking, pull-down, surface plasmon resonance-binding, cellular thermal shift, and ATPase assays were used to study the targets of DCZ5417. Bioinformatic, genetic, and pharmacological approaches were used to elucidate the mechanisms associated with DCZ5417 activity.ResultsWe confirmed a highly potent interaction between DCZ5417 and TRIP13. DCZ5417 inhibited the ATPase activity of TRIP13, and its anti-MM activity was found to depend on TRIP13. A mechanistic study verified that DCZ5417 suppressed cell proliferation by targeting TRIP13, disturbing the TRIP13/YWHAE complex and inhibiting the ERK/MAPK signaling axis. DCZ5417 also showed a combined lethal effect with traditional anti-MM drugs. Furthermore, the tumor growth-inhibitory effect of DCZ5417 was demonstrated using in vivo tumor xenograft models.ConclusionsDCZ5417 suppresses MM progression in vitro, in vivo, and in primary cells from drug-resistant patients, affecting cell proliferation by targeting TRIP13, destroying the TRIP13/YWHAE complex, and inhibiting ERK/MAPK signaling. These results imply a new and effective therapeutic strategy for MM treatment. |
| WOS关键词 | TRIP13 ; ATPASE |
| 资助项目 | National Natural Science Foundation of China |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| 出版者 | BMC |
| WOS记录号 | WOS:001114095000001 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/308365]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhu, Weiliang; Shi, Jumei |
| 作者单位 | 1.Shanghai Univ Tradit Chinese Med, Shanghai 201203, Peoples R China 2.Ningbo Univ, Affiliated Peoples Hosp, Dept Hematol, Ningbo 315000, Peoples R China 3.Tongji Univ, Shanghai Peoples Hosp 10, Dept Hematol, Sch Med, Shanghai 200072, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Tongji Univ, Shanghai East Hosp, Sch Med, Dept Hematol, Shanghai 200120, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Yingcong,Dong, Sanfeng,Hu, Ke,et al. The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway[J]. JOURNAL OF TRANSLATIONAL MEDICINE,2023,21(1):17. |
| APA | Wang, Yingcong.,Dong, Sanfeng.,Hu, Ke.,Xu, Li.,Feng, Qilin.,...&Shi, Jumei.(2023).The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway.JOURNAL OF TRANSLATIONAL MEDICINE,21(1),17. |
| MLA | Wang, Yingcong,et al."The novel norcantharidin derivative DCZ5417 suppresses multiple myeloma progression by targeting the TRIP13-MAPK-YWHAE signaling pathway".JOURNAL OF TRANSLATIONAL MEDICINE 21.1(2023):17. |
入库方式： OAI收割
来源：上海药物研究所
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