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Small Molecule Inhibitors of Programmed Cell Death Ligand 1 (PD-L1): A Patent Review (2019-2021)
Jingjing Deng1, Zhengqi Cheng2, Juyang Long2
1Department of Molecular Genetics, University of Groningen, Groningen, Netherlands.
Introduction:
The blockade of immune checkpoints, especially the PD-1/PD-L1 pathway with therapeutic antibodies, has shown success in treating cancers in recent years. Seven monoclonal antibodies (mAbs) targeting PD-1 or PD-L1 have been approved by FDA. However, mAbs exhibit several disadvantages as compared to small molecules such as poor permeation, high manufacturing costs, immunogenicity as well as lacking oral bioavailability. Recently, small-molecule inhibitors targeting PD-L1 have been disclosed with the ability to modulate the PD-1/PD-L1 pathway.
Areas Covered:
The authors reviewed small molecules targeting PD-L1 that block the PD-1/PD-L1 protein-protein interaction for the treatment of various diseases.
Expert Opinion:
Compared with mAbs, PD-1/PD-L1 small-molecule inhibitors show several advantages such as improved tissue penetration, low immunogenicity, well-understood formulation and lower manufacturing costs. They can serve as complementary or synergistically with mAbs for immune therapy. However, at this time most of the reported inhibitors are still inferior to therapeutic antibodies in their inhibitory activities due to smaller molecular weight. Therefore, better small molecules need to be developed to improve their potencies. Moreover, although several PD-L1 small-molecule inhibitors have shown excellent preclinical results, their safety and efficacy in the clinic still awaits further validation.
Insights
Small-molecule inhibitors targeting programmed cell death protein 1 ligand 1 (PD-L1) offer advantages over antibodies for cancer immunotherapy. Further development is needed to enhance their potency and clinical validation.
Area of Science:
- Oncology
- Immunology
- Medicinal Chemistry
Background:
- Immune checkpoint blockade, particularly targeting the PD-1/PD-L1 pathway with monoclonal antibodies (mAbs), has advanced cancer treatment.
- Current therapeutic antibodies face limitations including poor tissue penetration, high costs, immunogenicity, and lack of oral bioavailability.
Purpose of the Study:
- To review small-molecule inhibitors targeting PD-L1 and their potential to modulate the PD-1/PD-L1 pathway.
- To compare the advantages and disadvantages of small-molecule inhibitors versus mAbs for cancer immunotherapy.
Main Methods:
- Literature review of small molecules designed to inhibit PD-L1 and block PD-1/PD-L1 protein-protein interactions.
- Analysis of preclinical data and expert opinions on the efficacy and challenges of PD-L1 small-molecule inhibitors.
Main Results:
- Small-molecule inhibitors offer improved tissue penetration, lower immunogenicity, and reduced manufacturing costs compared to mAbs.
- These inhibitors can potentially complement or synergize with existing antibody-based immunotherapies.
Conclusions:
- While promising, current small-molecule PD-L1 inhibitors generally exhibit lower potency than therapeutic antibodies due to their smaller molecular size.
- Further research and development are crucial to enhance the efficacy of small molecules and validate their clinical safety and effectiveness.
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