2. Academic Validation
  3. Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells

Discovery of Urea Derivatives of Celastrol as Selective Peroxiredoxin 1 Inhibitors against Colorectal Cancer Cells

  • J Med Chem. 2024 May 9;67(9):7176-7196. doi: 10.1021/acs.jmedchem.4c00023.
Yang Li 1,  Yuyuan Zhu 2 3,  Fan-Fan Shang 1,  Lin Xu 1 4,  Defang Jiang 2 3,  Bin Sun 1 4,  Lei Zhang 4,  Cheng Luo 2 3,  Ao Zhang 1,  Hao Zhang 5,  Chunyong Ding 1 6
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Chemical Biology Research Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 School of Pharmaceutical Sciences, Zunyi Medical University, Guizhou 563000, China.
  • 5 Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 6 Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 201203, China.
PMID: 38679872 DOI: 10.1021/acs.jmedchem.4c00023
Abstract

Peroxiredoxin (PRDX1) is a tumor-overexpressed antioxidant Enzyme for eliminating excessive Reactive Oxygen Species (ROS) to protect tumor cells from oxidative damage. Herein, a series of celastrol urea derivatives were developed based on its cocrystal structure with PRDX1, with the aim of pursuing a PRDX1-specific inhibitor. Among them, derivative 15 displayed potent anti-PRDX1 activity (IC50 = 0.35 μM) and antiproliferative potency against colon Cancer cells. It covalently bound to Cys-173 of PRDX1 (KD = 0.37 μM), which was secured by the cocrystal structure of PRDX1 with an analogue of 15 while exhibiting weak inhibitory effects on PRDX2-PRDX6 (IC50 > 50 μM), indicating excellent PRDX1 selectivity. Treatment with 15 dose-dependently decreased the mitochondria membrane potential of SW620 cells, probably due to ROS induced by PRDX1 inhibition, leading to cell Apoptosis. In colorectal Cancer cell xenograft model, it displayed potent antitumor efficacy with superior safety to celastrol. Collectively, 15 represents a promising PRDX1 selective inhibitor for the development of anticolorectal Cancer agents.

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