Development of small-molecule immune checkpoint inhibitors of PD-1/PD-L1 as a new therapeutic strategy for tumour immunotherapy

J Drug Target. 2019 Mar;27(3):244-256. doi: 10.1080/1061186X.2018.1440400. Epub 2018 Feb 20.


Cancer immunotherapy has been increasingly utilised to treat advanced malignancies. The signalling network of immune checkpoints has attracted considerable attention. Immune checkpoint inhibitors are revolutionising the treatment options and expectations for patients with cancer. The reported clinical success of targeting the T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immune modulation. Indeed, antibodies binding to PD-1 or PD-L1 have shown remarkable efficacy. However, antibody drugs have many disadvantages, such as their production cost, stability, and immunogenicity and, therefore, small-molecule inhibitors of PD-1 and its ligand PD-L1 are being introduced. Small-molecule inhibitors could offer inherent advantages in terms of pharmacokinetics and druggability, thereby providing additional methods for cancer treatment and achieving better therapeutic effects. In this review, we first discuss how PD-1/PD-L1-targeting inhibitors modulate the relationship between immune cells and tumour cells in tumour immunotherapy. Second, we discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with immunotherapy and targeted therapy. Third, this review is the first to summarise the current clinical and preclinical evidence regarding small-molecule inhibitors of the PD-1/PD-L1 immune checkpoint, considering features and responses related to the tumours and to the host immune system.

Trial registration: NCT02812875.

Keywords: PD-1/PD-L1 immune checkpoint; Small-molecule inhibitors; clinical and preclinical research; targeted therapy; tumour immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Immunological / administration & dosage*
  • Antineoplastic Agents, Immunological / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology
  • Humans
  • Immunotherapy / methods*
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology


  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor

Associated data