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  3. Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer

Discovery and optimization of indirubin derivatives as novel ferroptosis inducers for the treatment of colon cancer

  • Eur J Med Chem. 2023 Sep 28:261:115829. doi: 10.1016/j.ejmech.2023.115829.
Jiang-Min Zhu 1,  Chen Chen 1,  Min Kong 1,  Ling Zhu 1,  Ya-Lin Li 1,  Jian-Fei Zhang 1,  Zhan-Peng Yu 1,  Shi-Shu Xu 1,  Ling-Yi Kong 2,  Jian-Guang Luo 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, People's Republic of China. Electronic address: luojg@cpu.edu.cn.
PMID: 37801824 DOI: 10.1016/j.ejmech.2023.115829
Abstract

Glutathione Peroxidase 4 (GPX4) is an essential antioxidant Enzyme that negatively regulates Ferroptosis. To exploit novel GPX4 inhibitors, we designed and synthesized 32 indirubin derivatives. Compound 31 exhibited the strongest antitumor activity against HCT-116 cells (IC50 = 0.49 ± 0.02 μM). Further studies suggested that 31 could induce Ferroptosis in colon Cancer cells and its cytotoxic activity could be reversed by Ferroptosis inhibitors. Mechanism research showed that 31 promoted the degradation of GPX4, causing the accumulation of lipid ROS to induce Ferroptosis. Animal experiments also proved that 31 could inhibit the growth of colon Cancer cells in vivo and reduce the expression of GPX4 in tumor tissues. These results indicated that compound 31 had potential as a novel Ferroptosis inducer agent for colon Cancer.

Keywords

Colon cancer; Ferroptosis; GPX4; Indirubin derivatives; Lipid ROS.

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