Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2.

Autor: Li, Wenjie, Mei, Wenyi, Jiang, Hewei, Wang, Jie, Li, Xiaoli, Quan, Lina, Diao, Yanyan, Ma, Yanni, Fan, Sisi, Xie, Zhuwei, Gong, Mengdie, Zhu, Huan, Bi, Dewen, Zhang, Feng, Ma, Lei, Zhang, Jian, Gao, Yufeng, Paschalidis, Aris, Lin, Honghuang, Liu, Fangfang
Zdroj: SCIENCE CHINA Life Sciences; Jan2025, Vol. 68 Issue 1, p189-203, 15p
Abstrakt: Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction. Furthermore, we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction. Subsequently, mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2, inhibiting the recruitment of SHP-2 by PD-1. Taken together, our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors. In addition, our success in target recognition provides a paradigm of target identification and confirmation for natural products. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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