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Recent Pat Anticancer Drug Discov. 2018 Oct 29. doi: 10.2174/1574892813666181029142812. [Epub ahead of print]

Novel Small Molecule Inhibitors of Programmed Cell Death (PD)-1, and its Ligand, PD-L1 in Cancer Immunotherapy: A review update of Patent Literature.

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Department of Bioscience and Biotechnology, Sejong University, Gwangjin-gu, Seoul 05006. Korea.
College of Biomedical and Health Sciences, Konkuk University, Chungju 27478. Korea.



In the last few decades, cancer immunotherapy has been extensively researched, and novel checkpoint signaling mechanisms involving programmed death (PD)-1 and PD-ligand 1 (PD-L1) receptors have been targeted. The PD-1/PD-L1 binding and interaction play a critical role in the development of malignancies.


The present review focuses on recent patents on the pharmacological and biological cancer-regulating properties of PD-1/PD-L1 inhibitors involved in immunotherapeutic cancer drug development.


Thorough patent literature search published during the last seven years, including the World Intellectual Property Organization (WIPO®), United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents, to identify PD-1/PD-L1-targeting small molecule immunomodulators.


Several small molecule PD-1/PD-L1 inhibitors were patented for regulation of tumor progression by academic and industry-associated investigators. Most of the claimed patents have been validated and confined to in vitro and in vivo mouse models limiting their entry into clinical settings. Majority of the patents are claimed by the researchers at Aurigene Ltd. (India) on novel peptidomimetic compounds. Macrocyclic and heterocyclic derivatives were more efficient in regulating the PD-1/PD-L1 protein-protein binding and interaction compared to those of the approved monoclonal antibodies.


PD-1/PD-L1 inhibitors show significant anti-cancer responses as stand-alone agents and in combination with other cancer therapies. More efficient experimental studies and clinical trials are necessary to evaluate the host-tumor cells' interactions. Understanding the cancer microenvironment, identifying specific biomarkers and X-ray crystalline structures of PD-1/PD-L1 complexes, including molecular and genomic signature studies are essential to determine the feasibility of PD-1/PD-L1 inhibitors for development into drug-like cancer immunotherapeutics.


PD-1/PD-L1 signaling ; cancer; immune checkpoints; immunomodulatory; immunotherapy; patents

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