Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?
文献类型：期刊论文
| 作者 | Yu, Qing1,2,3,4; Sun, Yi3,4 |
| 刊名 | DRUG DESIGN DEVELOPMENT AND THERAPY
 |
| 出版日期 | 2021 |
| 卷号 | 15 |
| 关键词 | anti-cancer drug cullin-RING E3 ligases natural product high-throughput screen neddylation small-molecule inhibitors |
| ISSN号 | 1177-8881 |
| DOI | 10.2147/DDDT.S286373 |
| 通讯作者 | Sun, Yi(yisun@zju.edu.cn) |
| 英文摘要 | Cullin-RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases, responsible for about 20% of the protein degradation by the ubiquitin-proteasome system (UPS). Given their vital roles in multiple cellular processes, and over-activation in many human cancers, CRLs are validated as promising targets for anti-cancer therapies. Activation of CRLs requires cullin neddylation, a process catalysed by three neddylation enzymes. Recently, our group established an AlphaScreen-based in vitro cullin neddylation assay and employed it for high-throughput screening to search for small-molecule inhibitors targeting cullin neddylation. During our pilot screen, gossypol, a natural product extracted from cottonseeds, was identified as one of the most potent neddylation inhibitors of cullin-1 and cullin-5. We further demonstrated that gossypol blocks cullin neddylation by binding to cullin-1/-5 to inactivate CRL1/5 ligase activity, leading to accumulation of MCL-1 and NOXA, the substrates of CRL1 and CRL5, respectively. The combination of gossypol and an MCL-1 inhibitor synergistically enhanced the anti-proliferative effect in multiple human cancer cell lines. Our study unveiled a rational combination of two previously known inhibitors of the Bcl-2 family for enhanced anti-cancer efficacy and identified a novel activity of gossypol as an inhibitor of CRL1 and CRL5 E3s, thus providing a new possibility in the development of novel CRL inhibitors for anti-cancer therapy. |
| WOS关键词 | PHASE-II ; PROTEASOME INHIBITORS ; CANCER ; AT-101 ; RESISTANCE ; INCREASES ; CELLS ; MCL-1 ; NOXA ; SENSITIVITY |
| 资助项目 | National Key R&D Program of China[2016YFA0501800] ; National Natural Science Foundation of China[81572718] ; National Natural Science Foundation of China[81630076] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000605659500001 |
| 出版者 | DOVE MEDICAL PRESS LTD |
| 资助机构 | National Key R&D Program of China ; National Natural Science Foundation of China |
| 源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/120071]  |
| 专题 | 中国科学院合肥物质科学研究院 |
| 通讯作者 | Sun, Yi |
| 作者单位 | 1.Chinese Acad Sci, Inst Basic Med & Canc IBMC, Zhejiang Canc Hosp, Canc Hosp,Univ Chinese Acad Sci,Dept Head & Neck, Hangzhou, Zhejiang, Peoples R China 2.Key Lab Head & Neck Canc Translat Res Zhejiang Pr, Hangzhou, Zhejiang, Peoples R China 3.Zhejiang Univ, Sch Med, Affiliated Hosp 2, Canc Inst, 268 Kaixuan Rd, Hangzhou, Zhejiang, Peoples R China 4.Zhejiang Univ, Sch Med, Inst Translat Med, 268 Kaixuan Rd, Hangzhou, Zhejiang, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yu, Qing,Sun, Yi. Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?[J]. DRUG DESIGN DEVELOPMENT AND THERAPY,2021,15. |
| APA | Yu, Qing,&Sun, Yi.(2021).Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?.DRUG DESIGN DEVELOPMENT AND THERAPY,15. |
| MLA | Yu, Qing,et al."Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?".DRUG DESIGN DEVELOPMENT AND THERAPY 15(2021). |
入库方式： OAI收割
来源：合肥物质科学研究院
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。