Ribonucleotide reductase holoenzyme inhibitor COH29 interacts with deubiquitinase ubiquitin-specific protease 2 and downregulates its substrate protein cyclin D1
文献类型：期刊论文
| 作者 | Zhu, Mengying1,2; Wang, Hui1; Ding, Yiluan1; Yang, Yuanyuan1; Xu, Zhuo1,2; Shi, Li1; Zhang, Naixia1,2
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| 刊名 | FASEB JOURNAL
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| 出版日期 | 2022-05-01 |
| 卷号 | 36期号:5页码:21 |
| 关键词 | COH29 cyclin D1 deubiquitinase inhibitor USP2 |
| ISSN号 | 0892-6638 |
| DOI | 10.1096/fj.202101914RR |
| 通讯作者 | Shi, Li(shili@simm.ac.cn) ; Zhang, Naixia(nxzhang@simm.ac.cn) |
| 英文摘要 | USP2 contributes to the quality control of multiple oncogenic proteins including cyclin D1, Mdm2, Aurora-A, etc., and it is a potential target for anti-cancer drug development. However, currently only a few inhibitors with moderate inhibition activities against USP2 have been discovered. USP2-targeted active compounds with either new scaffolds or enhanced activities are in need. Here in this study, Ub-AMC hydrolysis assay-based screening against similar to 4000 commercially available drugs and drug candidates was performed to identify USP2-targeted inhibitors. COH29, which was originally developed as an anti-cancer agent by blocking the function of human ribonucleotide reductase (RNR, IC50 = 16 mu M), was found to exhibit an inhibition activity against USP2 with the IC50 value at 2.02 +/- 0.16 mu M. The following conducted biophysical and biochemical experiments demonstrated that COH29 could specifically interact with USP2 and inhibit its enzymatic activity in a noncompetitive inhibition mode (K-i = 1.73 +/- 0.14 mu M). Since COH29 shows similar inhibitory potencies against RNR (RRM2) and USP2, USP2 inhibition-dependent cellular consequences of COH29 are expected. The results of cellular assays confirmed that the application of COH29 could downregulate the level of cyclin D1 by enhancing its degradation via ubiquitin-proteasome system (UPS), and the modulation effect of COH29 on cyclin D1 is independent of RRM2. Since cyclin D1 acts as an oncogenic driver in human cancer, our findings suggest that USP2 might be a promising therapeutic target for cyclin D1-addicted cancers, and COH29 could serve as a starting compound for high selectivity inhibitor development against USP2. |
| WOS关键词 | CANCER-CELL GROWTH ; PATHWAY ; TARGET ; DEGRADATION ; METASTASIS ; STABILIZES ; MECHANISMS ; DISCOVERY ; DISTINCT ; ARREST |
| 资助项目 | National Natural Science Foundation of China (NSFC)[21977105] ; National Natural Science Foundation of China (NSFC)[32000890] ; National Natural Science Foundation of China (NSFC)[32171220] ; National Natural Science Foundation of China (NSFC)[22107111] ; Shanghai Municipal Science and Technology Major Project |
| WOS研究方向 | Biochemistry & Molecular Biology ; Life Sciences & Biomedicine - Other Topics ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000787876900001 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/299514]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Shi, Li; Zhang, Naixia |
| 作者单位 | 1.Chinese Acad Sci, Analyt Res Ctr Organ & Biol Mol, Shanghai Inst Mat Med, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhu, Mengying,Wang, Hui,Ding, Yiluan,et al. Ribonucleotide reductase holoenzyme inhibitor COH29 interacts with deubiquitinase ubiquitin-specific protease 2 and downregulates its substrate protein cyclin D1[J]. FASEB JOURNAL,2022,36(5):21. |
| APA | Zhu, Mengying.,Wang, Hui.,Ding, Yiluan.,Yang, Yuanyuan.,Xu, Zhuo.,...&Zhang, Naixia.(2022).Ribonucleotide reductase holoenzyme inhibitor COH29 interacts with deubiquitinase ubiquitin-specific protease 2 and downregulates its substrate protein cyclin D1.FASEB JOURNAL,36(5),21. |
| MLA | Zhu, Mengying,et al."Ribonucleotide reductase holoenzyme inhibitor COH29 interacts with deubiquitinase ubiquitin-specific protease 2 and downregulates its substrate protein cyclin D1".FASEB JOURNAL 36.5(2022):21. |
入库方式： OAI收割
来源：上海药物研究所
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