From monoclonal antibodies to small molecules: the development of inhibitors targeting the PD-1/PD-L1 pathway

•Cancer immunotherapy was chosen as the most important breakthrough in 2013 by the Science.•Two monoclonal antibodies targeting the PD-1/PD-L1 pathway have been approved recently.•The monoclonal antibodies, peptides and patented small molecules are discussed in this article.•The PD-1/PD-L1 interactions are illustrated, which is helpful for the rational drug design. Cancer immunotherapy has made an extraordinary journey from bench to bedside. Blocking the interactions between programmed cell death protein 1 (PD-1) and its ligand, PD-L1, has emerged as a promising immunotherapy for treating cancer. Here, we review the development of drugs targeting the PD-1/PD-L1 pathway. We discuss the monoclonal antibodies (mAbs) approved or in clinical trials, peptides and patented small molecules developed against this pathway. Such compounds have the potential to treat cancer as well as chronic virological diseases. We also detail PD-1/PD-L1 interactions, an understanding of which will be useful for the rational design of small-molecule therapeutics that disrupt the PD-1/PD-L1 pathway. It is likely that more mAbs targeting the PD-1/PD-L1 pathway will be approved for the treatment of a range of cancers. By contrast, it is likely to be more difficult to successfully develop small molecules or peptides and for them to reach the clinic.