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Updated: Jan 15, 2026
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Novel PD-L1 Small-Molecule Inhibitors Advancing Cancer Immunotherapy
Annoor Awadasseid1,2,3, Mengda Wu1,3, Feng Zhang1,3
1Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Deqing, 313299, China.
Introduction:
The emergence of immune checkpoint inhibitors has revolutionized the treatment of cancer. Among these, the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis remains a critical target. However, resistance to current biologics necessitates the development of novel Small- Molecule Inhibitors (SMIs) with distinct mechanisms and improved pharmacological profiles. This review provides a comprehensive analysis of recent progress in PD-L1-targeting SMIs, including original compounds from our laboratory.
Methods:
We conducted a structured literature review using electronic databases such as PubMed, Scopus, and Web of Science. Articles published between 2015 and 2025 were included based on relevance to small-molecule PD-L1 inhibitors in cancer immunotherapy. Key data were extracted and synthesized regarding molecular design strategies, mechanisms of action, pharmacokinetics, and therapeutic efficacy. Compounds synthesized in our laboratory (Compounds 5-10 [A56]) were evaluated using in vitro assays, including PD-L1/PD-1 binding inhibition, cancer cell viability assays, and gene expression profiling.
Results:
Recent SMIs exhibit diverse functional profiles: direct blockade of PD-1/PD-L1 interaction, intracellular PD-L1 modulation, and transcriptional downregulation. Notably, Compound 7 demonstrated significant suppression of PD-L1 mRNA expression, while Compounds 9 and 10 (A56) achieved nanomolar-level binding affinity. These findings reflect innovative approaches to overcoming immune resistance and enhancing antitumor responses.
Discussions:
Our findings underscore a trend toward multifunctional PD-L1-targeting SMIs that operate through both extracellular and intracellular mechanisms. Compounds from our laboratory represent potential leads for further optimization and clinical translation. However, challenges remain regarding oral bioavailability, metabolic stability, and immune-related adverse events.
Conclusion:
Small-molecule PD-L1 inhibitors offer a promising avenue for expanding cancer immunotherapy. Our review highlights key advances and introduces novel small-molecule PD-L1 inhibitors with strong potential for future development, particularly in combination regimens.
Insights
Novel small-molecule inhibitors targeting the PD-L1/PD-1 axis offer new cancer immunotherapy strategies. Our research highlights innovative compounds with potential to overcome resistance and improve treatment outcomes.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Immune checkpoint inhibitors, particularly targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, have transformed cancer treatment.
- Resistance to current biologics necessitates the development of novel small-molecule inhibitors (SMIs) with improved pharmacological profiles and distinct mechanisms of action.
Purpose of the Study:
- To review recent advancements in PD-L1-targeting SMIs for cancer immunotherapy.
- To present novel small-molecule PD-L1 inhibitors developed in our laboratory.
Main Methods:
- A structured literature review of articles published between 2015 and 2025 on small-molecule PD-L1 inhibitors.
- In vitro evaluation of novel compounds (Compounds 5-10 [A56]) for PD-L1/PD-1 binding inhibition, cancer cell viability, and gene expression.
Main Results:
- Recent SMIs demonstrate diverse mechanisms, including direct PD-1/PD-L1 blockade, intracellular PD-L1 modulation, and transcriptional downregulation.
- Compound 7 significantly suppressed PD-L1 mRNA expression; Compounds 9 and 10 (A56) exhibited nanomolar binding affinity.
- These findings indicate innovative strategies for overcoming immune resistance and enhancing antitumor responses.
Conclusions:
- A trend towards multifunctional PD-L1-targeting SMIs with both extracellular and intracellular mechanisms is evident.
- Novel compounds from our laboratory show promise for further optimization and clinical translation.
- Challenges in oral bioavailability, metabolic stability, and immune-related adverse events require further investigation.
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