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Updated: Jun 23, 2025
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
An updated patent review on PD-1/PD-L1 antagonists (2022-present)
Wiktor Uzar1,2, Beata Kaminska1,2, Hubert Rybka1,2
1Faculty of Chemistry, Jagiellonian University, Cracow, Poland.
Introduction:
PD-L1, via its interactions with PD-1, constitutes a key immune checkpoint that allows cancer cells to escape immune surveillance. Targeting PD-1/PD-L1 with monoclonal antibodies (mAbs) led to spectacular success in clinical oncology. However, the inherent limitations of mAbs and increasing findings about immune-related adverse events (iRAEs) prompted intense research in the field of small-molecule inhibitors of PD-L1.
Areas Covered:
This review covers inhibitors of PD-L1 reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2022-2023 period. This review provides a landscape of available inhibitors, including their chemical structures, activity, and stage of development.
Expert Opinion:
Small-molecule inhibitors impairing PD-L1/PD-1 interaction represent an attractive alternative to mAbs. In recent years, the field of small-molecule and macrocyclic inhibitors targeting PD-L1 has grown rapidly. The majority (if not all) of small-molecule inhibitors developed recently, similarly to their predecessors, act through a dimerization mechanism of PD-L1, followed by its internalization into the cytosol. In contrast, macrocyclic peptides act purely through a competition mechanism known as protein-protein interaction inhibitors. The ongoing clinical trials should ultimately reveal which strategy has real clinical potential and may complement or even replace mAbs-based therapies.
Insights
Small-molecule inhibitors targeting programmed cell death-ligand 1 (PD-L1) offer an alternative to antibody therapies. Research is rapidly advancing, with new inhibitors showing promise in clinical trials for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Programmed cell death-ligand 1 (PD-L1) is a key immune checkpoint enabling cancer cells to evade immune surveillance.
- Monoclonal antibodies (mAbs) targeting PD-1/PD-L1 have shown success in cancer treatment but have limitations and can cause immune-related adverse events (iRAEs).
- This has spurred research into small-molecule inhibitors of PD-L1 as an alternative therapeutic strategy.
Purpose of the Study:
- To review small-molecule and macrocyclic inhibitors of PD-L1 reported in patents from 2022-2023.
- To provide a landscape of these inhibitors, including their chemical structures, activity, and developmental stages.
- To assess the potential of these inhibitors as alternatives or complements to current mAb-based therapies.
Main Methods:
- Systematic review of patents from the World Intellectual Property Organization and European Patent Office (2022-2023).
- Analysis of reported chemical structures, biological activity, and clinical development status of PD-L1 inhibitors.
- Comparison of small-molecule and macrocyclic inhibitor mechanisms of action.
Main Results:
- A growing number of small-molecule and macrocyclic inhibitors targeting PD-L1 have been reported in recent patents.
- Most small-molecule inhibitors function by inducing PD-L1 dimerization and subsequent internalization.
- Macrocyclic peptides act as protein-protein interaction inhibitors by competing for PD-L1/PD-1 binding.
Conclusions:
- Small-molecule inhibitors represent a promising alternative to mAbs for targeting the PD-1/PD-L1 pathway.
- Different mechanisms of action (dimerization vs. competitive inhibition) are employed by small-molecule and macrocyclic inhibitors.
- Ongoing clinical trials are crucial to determine the therapeutic potential and clinical utility of these novel PD-L1 inhibitors.
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