Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1
文献类型：期刊论文
| 作者 | Xu, Heng7,8; Zhao, Hongfang5,6; Ding, Chunyong4; Jiang, Defang3; Zhao, Zijie8; Li, Yang4; Ding, Xiaoyu2; Gao, Jing7; Zhou, Hu7 ; Luo, Cheng3,7,8
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| 刊名 | Signal Transduction and Targeted Therapy
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| 出版日期 | 2023-02-03 |
| 卷号 | 8期号:3页码:1159-1174 |
| ISSN号 | 2095-9907 |
| DOI | 10.1038/s41392-022-01231-4 |
| 文献子类 | Article |
| 英文摘要 | As a terpenoids natural product isolated from the plant Thunder God Vine, Celastrol is widely studied for its pharmacological activities, including anti-tumor activities. The clinical application of Celastrol is strictly limited due to its severe side effects, whereas previously revealed targets and mechanism of Celastrol seldom reduce its in vivo toxicity via structural optimization. Target identification has a far-reaching influence on the development of innovative drugs, and omics data has been widely used for unbiased target prediction. However, it is difficult to enrich target of specific phenotype from thousands of genes or proteins, especially for natural products with broad promising activities. Here, we developed a text-mining-based web-server tool to enrich targets from omics data of inquired compounds. Then peroxiredoxin 1 (PRDX1) was identified as the ROS-manipulating target protein of Celastrol in colorectal cancer. Our solved high-resolution crystal structure revealed the unique covalent binding mode of Celastrol with PRDX1. New derivative compound 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized based on crystal structure analysis. Both Celastrol and 19-048 effectively suppressed the proliferation of colorectal cancer cells. The anti-tumor efficacy of Celastrol and 19-048 was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells. Several downstream genes of p53 signaling pathway were dramatically up-regulated with Celastrol or 19-048 treatment. Our findings reveal that the side effects of Celastrol could be reduced via structural modification, and PRDX1 inhibition is promising for the treatment of colorectal cancer. |
| 语种 | 英语 |
| CSCD记录号 | CSCD:7438082 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309630]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Ao; Xu, Ying; Zhang, Hao |
| 作者单位 | 1.State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China 2.University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China; 3.School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia, Nanjing 210023 Jiangsu, China; 4.Pharm-X center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; 5.Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; 6.CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; 7.Chemical Biology Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 8.School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; |
| 推荐引用方式 GB/T 7714 | Xu, Heng,Zhao, Hongfang,Ding, Chunyong,et al. Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1[J]. Signal Transduction and Targeted Therapy,2023,8(3):1159-1174. |
| APA | Xu, Heng.,Zhao, Hongfang.,Ding, Chunyong.,Jiang, Defang.,Zhao, Zijie.,...&Zhang, Hao.(2023).Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1.Signal Transduction and Targeted Therapy,8(3),1159-1174. |
| MLA | Xu, Heng,et al."Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1".Signal Transduction and Targeted Therapy 8.3(2023):1159-1174. |
入库方式： OAI收割
来源：上海药物研究所
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