2. Academic Validation
  3. Indirubin derivatives as bifunctional molecules inducing DNA damage and targeting PARP for the treatment of cancer

Indirubin derivatives as bifunctional molecules inducing DNA damage and targeting PARP for the treatment of cancer

  • Eur J Med Chem. 2023 Dec 5:261:115843. doi: 10.1016/j.ejmech.2023.115843.
Siyuan Wan 1,  Xinye Chen 1,  Fucheng Yin 1,  Shang Li 1,  Yonglei Zhang 1,  Heng Luo 1,  Zhongwen Luo 1,  Ningjie Cui 1,  Yifan Chen 1,  Xinxin Li 1,  Lingyi Kong 2,  Xiaobing Wang 3
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
  • 2 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: cpu_lykong@126.com.
  • 3 Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: xbwang@cpu.edu.cn.
PMID: 37832229 DOI: 10.1016/j.ejmech.2023.115843
Abstract

Based on the facts that significant synergistic effect existed between PARP inhibitors and DNA damage agents and the DNA damage caused by indirubin's derivatives, we herein adopted the strategy to combine the pharmacophores of PARP inhibitors and the unique scaffold of indirubin to design a series of bifunctional molecules inducing DNA damage and targeting PARP. After SAR studies, the most potent compound 12a, encoded as KWWS-12a, exhibited improved inhibitory effect against PARP1 compared with PARP1 Inhibitor Olaparib (IC50 = 1.89 nM vs 7.48 nM) and enhanced antiproliferative activities than the combination of Olaparib and indirubin-3'-monoxime towards HCT-116 cells (IC50 = 0.31 μM vs 1.37 μM). In the normal NCM-460 cells, 12a showed low toxicity (IC50 > 60 μM). The mechanism research indicated that 12a could increase the levels of γH2AX concentration dependently, arrest the cell cycle in S phase and induce Apoptosis in HCT-116 cells. In vivo experiments showed that 12a displayed more significant antitumor potential than that of the positive controls. Our studies demonstrated that 12a could be a promising candidate for Cancer therapy.

Keywords

Cancer; DNA damage; Indirubin; Olaparib; PARP1.

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