Development of Inhibitors of the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Signaling Pathway

• Published in: Journal of medicinal chemistry Vol. 62; no. 4; pp. 1715 - 1730
• Main Authors: Wang, Tianyu, Wu, Xiaoxing, Guo, Changying, Zhang, Kuojun, Xu, Jinyi, Li, Zheng, Jiang, Sheng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28-02-2019
• Subjects: Amino Acid Sequence; Animals; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - therapeutic use; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - metabolism; Humans; Immunotherapy - methods; Neoplasms - drug therapy; Neoplasms - therapy; Peptides, Cyclic - therapeutic use; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; Signal Transduction - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00990

The clinical success of inhibitors targeting the PD-1/PD-L1 pathway has made this an active field in cancer immunotherapy. Currently, most drugs targeting this pathway are monoclonal antibodies. Small-molecule inhibitors as the alternative to monoclonal antibodies are expected to overcome the disadvantages of mAbs which include production difficulties and their long half-life. Recently, progress has been reported on anti-PD-1/PD-L1 small-molecule inhibitors. In this paper, we review the development of inhibitors targeting the PD-1/PD-L1 pathway, focusing mainly on peptide-based and nonpeptidic small-molecule inhibitors. The structures and the preclinical and clinical studies of several peptide-based small-molecule candidate compounds in clinical trials are discussed. We also illustrate the design strategies underlying reported nonpeptidic small-molecule inhibitors and provide insight into possible future exploration. Development of small-molecule drugs for anti-PD-1/PD-L1 activity with specific cancer applications is a promising and challenging prospect.