Identification of Epinastine as CD96/PVR inhibitor for cancer immunotherapy.

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. 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. 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. © 2025. The Author(s).

Citation

Xiangrui Zhang, Lihan Zhang, Beibei Li, Qingchao Wang, Peixin Chen, Ranran Shi, Xiuman Zhou, Xiaoshuang Niu, Wenjie Zhai, Yahong Wu, Wenhui Shen, Xiaowen Zhou, Wenshan Zhao. Identification of Epinastine as CD96/PVR inhibitor for cancer immunotherapy. BMC biology. 2025 Jan 27;23(1):27

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PMID: 39871281

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