2. Academic Validation
  3. Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy

Dual target PARP1/EZH2 inhibitors inducing excessive autophagy and producing synthetic lethality for triple-negative breast cancer therapy

  • Eur J Med Chem. 2023 Dec 17:265:116054. doi: 10.1016/j.ejmech.2023.116054.
Xinxin Li 1,  Cheng Wang 1,  Shang Li 1,  Fucheng Yin 1,  Heng Luo 1,  Yonglei Zhang 1,  Zhongwen Luo 1,  Yifan Chen 1,  Siyuan Wan 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: [email protected].
  • 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: [email protected].
PMID: 38134746 DOI: 10.1016/j.ejmech.2023.116054
Abstract

Currently available PARP inhibitors are mainly used for the treatment of BRCA-mutated triple-negative breast Cancer (TNBC), with a narrow application range of approximately 15% of patients. Recent studies have shown that EZH2 inhibitors have an obvious effect on breast Cancer xenograft models and can promote the sensitivity of ovarian Cancer cells to PARP inhibitors. Here, a series of new dual-target PARP1/EZH2 inhibitors for wild-BRCA type TNBC were designed and synthesized. SAR studies helped us identify compound 12e, encoded KWLX-12e, with good inhibitory activity against PARP1 (IC50 = 6.89 nM) and EZH2 (IC50 = 27.34 nM). Meanwhile, KWLX-12e showed an optimal cytotoxicity against MDA-MB-231 cells (IC50 = 2.84 μM) and BT-549 cells (IC50 = 0.91 μM), with no toxicity on normal breast cell lines. KWLX-12e also exhibited good antitumor activity with the TGI value of 75.94%, more effective than Niraparib plus GSK126 (TGI = 57.24%). Mechanistic studies showed that KWLX-12e achieved synthetic lethality indirectly by inhibiting EZH2 to increase the sensitivity to PARP1, and induced cell death by regulating excessive Autophagy. KWLX-12e is expected to be a potential candidate for the treatment of TNBC.

Keywords

EZH2; PARP; Synthetic lethality; Triple-negative breast cancer.

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