Discovery of novel anthraquinone-based P2X7R antagonist that reinvigorates anti-tumor immunity and overcomes PD-1 resistance in breast cancer

  • Eur J Med Chem. 2026 Oct 5:315:118924. doi: 10.1016/j.ejmech.2026.118924.
Chenyu Liang  1 ,  Simin Wang  2 ,  Xiaozhen Liu  2 ,  Xin Wang  2 ,  Benjun Yuan  2 ,  Xuyang Wang  3 ,  Wei Liu  4 ,  Tianyou Wang  5 ,  Chuanjun Song  6 ,  Yongfang Yao  7 ,  Yongtao Duan  8
Affiliations
  • 1. Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 2. College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China.
  • 3. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 4. Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China.
  • 5. Beijing Children's Hospital, Capital Medical University, Beijing, China.
  • 6. College of Chemistry, Zhengzhou University, Zhengzhou, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 7. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China; Pingyuan Laboratory, Zhengzhou, 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: [email protected].
  • 8. Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China; The Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, Henan, 450053, China. Electronic address: [email protected].
PMID: 42143940 DOI: 10.1016/j.ejmech.2026.118924
Abstract

The P2X7 Receptor (P2X7R) is critically involved in tumor progression by promoting Cancer cell proliferation, invasion, metastasis, and immune evasion. Through structure-based virtual screening of the TOPSCIENCE L1000 library, we identified pixantrone - an FDA-approved agent - as a promising lead compound targeting P2X7R. Leveraging its well-established safety profile and anthraquinone scaffold, we designed and synthesized a novel series of P2X7R antagonists. Among them, the optimized compound 17d displayed potent antagonistic activity (IC50 = 3.57 μM) and specific binding to P2X7R. In addition, 17d exhibited significant antiproliferative activity against MCF-7 cells (IC50 = 0.42 μM) and effectively inhibited their invasive and metastatic capabilities. Compound 17d also demonstrated favorable oral bioavailability and pharmacokinetic properties. Moveover, in a murine breast Cancer model, 17d significantly suppressed tumor growth and metastasis while promoting the activation of CD4 and CD8 T cells to enhance antitumor immunity. Notably, 17d acted synergistically with anti-PD-1 monoclonal antibody, overcoming resistance to anti-PD-1 therapy. These findings highlight 17d as a promising candidate for P2X7R-targeted Cancer therapy and underscore the value of repurposing FDA-approved drugs using structure-based approaches to accelerate the development of safer and more effective Anticancer agents.

Keywords
Antitumor immunity; Breast cancer; Drug repurposing; P2X7R antagonist; PD-1 resistance.
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