Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

Front Immunol. 2022 May 2:13:752065. doi: 10.3389/fimmu.2022.752065. eCollection 2022.


Pioneering success of antibodies targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has changed the outlook of cancer therapy. Although these antibodies show impressive durable clinical activity, low response rates and immune-related adverse events are becoming increasingly evident in antibody-based approaches. For further strides in cancer immunotherapy, novel treatment strategies including combination therapies and alternate therapeutic modalities are highly warranted. Towards this discovery and development of small molecule, checkpoint inhibitors are actively being pursued, and the efforts have culminated in the ongoing clinical testing of orally bioavailable checkpoint inhibitors. This review focuses on the small molecule agents targeting PD-1 checkpoint pathway for cancer immunotherapy and highlights various chemotypes/scaffolds and their characterization including binding and functionality along with reported mechanism of action. The learnings from the ongoing small molecule clinical trials and crucial points to be considered for their clinical development are also discussed.

Keywords: PD-L1 inhibitors; cancer immunotherapy; mechanism of action (MOA); small molecule PD-1/PD-L1 inhibitors; small molecule immunomodulators.

Publication types

  • Review

MeSH terms

  • Animals
  • Antibodies
  • B7-H1 Antigen* / antagonists & inhibitors
  • B7-H1 Antigen* / immunology
  • Humans
  • Immune Checkpoint Inhibitors* / pharmacology
  • Immunotherapy
  • Neoplasms*
  • Programmed Cell Death 1 Receptor*
  • Randomized Controlled Trials as Topic
  • Small Molecule Libraries* / pharmacology


  • Antibodies
  • B7-H1 Antigen
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Small Molecule Libraries