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Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Novel Selenium-Containing Small Molecule PD-L1 Inhibitors: Design, Synthesis, and Evaluation of the Antitumor
Jianwei Wang1,2, Shenwei Yu1,2, Liang Qian1,2
1Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Deqing 313299, China.
Journal of Medicinal Chemistry
|July 3, 2026
Summary
Novel selenium-containing small molecule SA13 effectively inhibits PD-1/PD-L1 interactions, showing significant tumor growth inhibition with no observable toxicity in preclinical models. This discovery highlights SA13 as a promising new antitumor agent.
Area of Science:
- Medicinal Chemistry
- Immunotherapy
- Structural Biology
Background:
- The programmed cell death protein 1 (PD-1) and its ligand PD-L1 pathway is a key regulator of the immune response, often exploited by tumors to evade immune surveillance.
- Developing small molecule inhibitors targeting the PD-1/PD-L1 interaction offers a promising strategy for cancer immunotherapy.
Purpose of the Study:
- To design, synthesize, and evaluate novel selenium-containing small molecules as potential inhibitors of the PD-1/PD-L1 interaction.
- To identify and characterize potent and safe small molecule inhibitors for cancer treatment.
Main Methods:
- Computer-aided drug design and structural optimization.
- Biophysical techniques including Homogeneous Time-Resolved Fluorescence (HTRF) and Surface Plasmon Resonance (SPR) to assess binding affinity.
- X-ray crystallography to determine the co-crystal structure of SA13 with human PD-L1.
- Cell-based assays to evaluate PD-L1 internalization and blockade of PD-1/PD-L1 interaction.
- In vivo efficacy studies using a Hu-PD-L1 MC38 mouse model.
Main Results:
- Compound SA13 was identified as a potent inhibitor of PD-1/PD-L1 interaction with IC50 of 5.2 ± 0.5 nM and Kd of 9.06 ± 1.25 nM.
- The co-crystal structure revealed a unique binding mode involving a selenomethyl group, explaining SA13's superior activity.
- SA13 effectively mediated PD-L1 internalization and blocked the PD-1/PD-L1 interaction in cell-based assays.
- SA13 demonstrated significant tumor growth inhibition (77.79% TGI) in a mouse model with no observable toxicity.
Conclusions:
- SA13 represents a novel class of selenium-containing small molecule inhibitors targeting the PD-1/PD-L1 pathway.
- The unique binding mode and potent inhibitory activity make SA13 a promising candidate for further development as an antitumor agent.
- SA13 exhibits favorable preclinical efficacy and safety profiles, warranting further clinical investigation.
