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

In recent years, immune checkpoint therapy headed by programmed death receptor 1 (PD-1) and programmed death receptor-ligand 1 (PD-L1) has been proven to be safe and effective. However, clinical studies showed that the response rate of PD-1/PD-L1 therapy is only 20%—30% due to the inherent defects of antibody drugs, such as high immunogenicity, poor tissue permeability and stability. A part of patients with primary resistance and secondary resistance limited the development of PD-1/PD-L1 immune checkpoint therapy. Therefore, the development of small-molecule inhibitors targeting PD-1/PD-L1 to circumvent the deficiencies of antibody drugs is prospective. 

“We set up a screening program of our in-house natural product database against PD-1/PD-L1 signaling and identified a natural pentacyclic triterpenoid, Pygenic Acid A (PA), from medicinal plant of Callicarpa arborea, as a PD-1 signaling inhibitor. Moreover, we found that PA exerts T cell-mediated immune anti-tumor activity by blocking PD-1 signaling in vivo and restores the effector function of T cells inhibited by PD-1/PD-L1.” said Dr. Wenjie Li, the co-first author for this work.

The researchers identified SHP-2 as a potential target of PA using the SPIDER method, and verified the direct interaction between PA and SHP-2 by a series of experiments, including pull-down assays, DARTS assays, SPR assays, molecular docking analysis and a series of single-point and multipoint mutagenesis experiments. Their study suggested that PA targets the phosphorylated PD-1 ITSM recognition site of SHP-2, resulting in competitively blocking the interaction of PD-1 with SHP-2, ultimately leading to the interruption of the PD-1/PD-L1 signal transduction.

“Our research provide a paradigm of target identification and confirmation for natural products.” said Professor Honglin Li, the co-corresponding author.

These new exciting results not only provide a potential candidate of PD-1 inhibitor, but also suggest that occupying the phosphorylated PD-1 ITSM recognition site of SHP-2 is a new route to develop PD-1 signaling inhibitors.

This work was supported in part by the National Natural Science Foundation of China (grants 81825020 and 82150208 to H.L.L; 82260682 to W.X.), the National Key R&D Program of China (2022YFC3400501, 2022YFC3400504), the Shanghai Science and Technology Commission Biomedical Science and Technology Support Special Project (grants 21S11907900 and 20S11901000 to Z.Z.) and Project of Yunnan Characteristic Plant Screening and R&D Service CXO Platform (2022YKZY001). Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-notch Young Professionals.

See the article:

Li, W., Mei, W., Jiang, H., et al. (2024). Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2. Sci China Life Sci, in press, https://doi.org/10.1007/s11427-024-2706-2