2. Academic Validation
  3. Discovery of precision targeting EZH2 degraders for triple-negative breast cancer

Discovery of precision targeting EZH2 degraders for triple-negative breast cancer

  • Eur J Med Chem. 2022 Aug 5:238:114462. doi: 10.1016/j.ejmech.2022.114462.
Cheng Wang 1,  Xinye Chen 1,  Xingchen Liu 1,  Dehua Lu 1,  Shang Li 1,  Lailiang Qu 1,  Fucheng Yin 1,  Heng Luo 1,  Yonglei Zhang 1,  Zhongwen Luo 1,  Ningjie Cui 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, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 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, 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, Nanjing, 210009, People's Republic of China. Electronic address: xbwang@cpu.edu.cn.
PMID: 35623249 DOI: 10.1016/j.ejmech.2022.114462
Abstract

EZH2 is usually overexpressed in TNBC and Other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (KD = 16.19 nM) and show good inhibitory effects on MDA-MB-231 (IC50 = 0.57 μM) and MDA-MB-468 (IC50 = 0.38 μM) cells. Compared with that of the GSK126, the growth inhibitory activities of U3i against these two TNBC cells increased by approximately 20- and 30-fold. Further studies showed that U3i can degrade PRC2 complex in TNBC cells, induce Apoptosis, and cause little damage to normal cells. Therefore, U3i is a potential Anticancer molecule for TNBC treatment.

Keywords

Apoptosis; Enhancer of zeste homolog 2; Polycomb repressive complex 2; Proteolysis targeting chimeras; Triple-negative breast cancer.

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