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

Abstract

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.

Figure 1

Compounds based on the biphenyl scaffold, originally identified by a conventional approach of screening compounds in an assay for prevention of the PD-1, PD-L1 interaction.

Figure 2

Representative structures of first-generation biphenyl derivatives and C₂ symmetric compounds targeting PD-L1.

Figure 3

Representative structures of modified biphenyl analogues without C₂ symmetry but with improved druggability.

Figure 4

Amino-acid-inspired small molecules mimicking the receptor–ligand interface identified in a functional assay.

Figure 5

Representative structures of amino-acid-inspired interface mimics targeting PD-L1.

Figure 6

Two distinct mechanisms leading to functional antagonism with reported small molecule PD-L1 inhibitors.