2. Academic Validation
  3. Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy

Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy

  • Bioorg Med Chem. 2023 Aug 15:91:117386. doi: 10.1016/j.bmc.2023.117386.
Xinye Chen 1,  Cheng Wang 1,  Dehua Lu 1,  Heng Luo 1,  Shang Li 1,  Fucheng Yin 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, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, 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 210009, 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 210009, China. Electronic address: [email protected].
PMID: 37379621 DOI: 10.1016/j.bmc.2023.117386
Abstract

Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28, encoded as KWCX-28, was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC50 = 1.86 µM), induced HCT-116 cells Apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.

Keywords

BRD4; EZH2; SAR; Solid tumor.

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