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

Tianyu Wang, Xiaoxing Wu, Changying Guo, Kuojun Zhang, Jinyi Xu, Zheng Li, Sheng Jiang

Research output: Contribution to journalReview articlepeer-review

95 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1715-1730
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number4
StatePublished - Feb 28 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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