1. Academic Validation
  2. AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition

AZD9291 inactivates the PRC2 complex to mediate tumor growth inhibition

  • Acta Pharmacol Sin. 2019 Dec;40(12):1587-1595. doi: 10.1038/s41401-019-0248-2.
Kai-Li Zhang 1 2 Qian-Qian Shen 1 Yan-Fen Fang 1 Yi-Ming Sun 1 Jian Ding 3 Yi Chen 4
Affiliations

Affiliations

  • 1 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jding@simm.ac.cn.
  • 4 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. ychen@simm.ac.cn.
Abstract

Deregulated Polycomb repressive complex 2 (PRC2) is intimately involved in tumorigenesis and progression, making it an invaluable target for epigenetic Cancer therapy. Disrupting the EZH2-EED interaction, which is required for PRC2 enzymatic activity, is a promising strategy for Cancer treatment. However, this kind of inhibitors are still limited. The in-cell protein-protein interaction screening was conducted for approximately 1300 compounds by NanoBRET technology. Co-immunoprecipitation (Co-IP), protein thermal shift assay (PTSA), and cellular thermal shift assay (CETSA) were performed to investigate the regulation of PRC2 by AZD9291. The anti-tumor effects of AZD9291 on breast Cancer (BC) cells and diffuse large B-cell lymphoma (DLBCL) cells were detected. MicroRNA array assay, luciferase reporter assay, and qRT-PCR were conducted to identify the interaction and regulation among AZD9291, EZH2, and miR-34a. We discovered that, AZD9291, a potent and selective EGFR inhibitor, disrupted the interaction of EZH2-EED, leading to impairment of PRC2 activity and downregulation of EZH2 protein. In addition, AZD9291 declined EZH2 mRNA expression via upregulating the expression of a tumor suppressor, miR-34a. Our results suggest that AZD9291 can serve as a lead compound for further development of antagonist of PRC2 protein-protein interactions and EZH2 mRNA may be a direct target of miR-34a through non-canonical base pairing.

Keywords

AZD9291; EZH2–EED; PRC2; miR-34a; non-canonical base pairing.

Figures
Products