Identification of Epinastine as CD96/PVR inhibitor for cancer immunotherapy

  • BMC Biol. 2025 Jan 27;23(1):27. doi: 10.1186/s12915-025-02132-y.
Xiangrui Zhang  #  1 ,  Lihan Zhang  #  2 ,  Beibei Li  1 ,  Qingchao Wang  1 ,  Peixin Chen  1 ,  Ranran Shi  3 ,  Xiuman Zhou  4 ,  Xiaoshuang Niu  4 ,  Wenjie Zhai  1  5 ,  Yahong Wu  1  5 ,  Wenhui Shen  6 ,  Xiaowen Zhou  7 ,  Wenshan Zhao  8
Affiliations
  • 1. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
  • 2. Department of Integrated Chinese and Western Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
  • 3. Department of Basic Medical Sciences, Luohe Medical College, Luohe, 462000, China.
  • 4. School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, Shenzhen, 518107, China.
  • 5. International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou University, Zhengzhou, 450001, China.
  • 6. Department of Head Neck and Thyroid, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
  • 7. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China. [email protected].
  • 8. School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China. [email protected].
  • # Contributed equally.
PMID: 39871281 DOI: 10.1186/s12915-025-02132-y
Abstract

Background: Poliovirus receptor (PVR) and its receptor system, including TIGIT, CD226, and CD96, play a pivotal role in orchestrating tumor immune evasion. Upon engagement with PVR on tumor cells, CD96 exerts inhibitory effects on the function of T cells and NK cells, thereby fostering tumor immune evasion. Therefore, screening of immune checkpoint inhibitors (ICIs) targeting the CD96/PVR pathway will provide promising candidates for tumor immunotherapy.

Results: In this investigation, we employed MOE software to conduct virtual screening of small molecules from the FDA-approved drug library. Our results demonstrated that Epinastine exhibited high affinity for CD96, thereby effectively disrupting the interaction between CD96 and PVR. In vitro co-culture experiments further revealed that Epinastine effectively restored the ability of Jurkat cells to secrete IL-2. In the MC38 tumor-bearing model, Epinastine significantly enhanced the infiltration of T cells and NK cells into the tumor site and augmented their secretion of IFN-γ, leading to effective suppression of tumor growth.

Conclusions: Our results demonstrated that the development of small molecule inhibitor Epinastine targeting CD96/PVR pathway, which proposed a promising strategy and drug candidate for Cancer Immunotherapy.

Keywords
CD96; Cancer immunotherapy; Immune checkpoint inhibitor; PVR; Small molecule.
Products