2. Academic Validation
  3. Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1

Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1

  • Signal Transduct Target Ther. 2023 Feb 3;8(1):51. doi: 10.1038/s41392-022-01231-4.
Heng Xu # 1 2,  Hongfang Zhao # 3 4,  Chunyong Ding # 5,  Defang Jiang 6,  Zijie Zhao 1,  Yang Li 5,  Xiaoyu Ding 7,  Jing Gao 2,  Hu Zhou 2,  Cheng Luo 1 2 6,  Guoqiang Chen 8,  Ao Zhang 9,  Ying Xu 10,  Hao Zhang 11 12
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 2 Chemical Biology Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 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.
  • 4 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.
  • 5 Pharm-X center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia, Nanjing, 210023, Jiangsu, China.
  • 7 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 8 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 9 Pharm-X center, College of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China. [email protected].
  • 10 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. [email protected].
  • 11 Chemical Biology Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 12 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 36732502 DOI: 10.1038/s41392-022-01231-4
Abstract

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.

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