Small Molecule Inhibitors in Cancer Immunotherapy

Small molecule inhibitors have emerged as a complementary strategy to antibody-based checkpoint blockade in cancer immunotherapy. By targeting key immune checkpoints such as the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, these low-molecular-weight compounds aim to restore antitumour T-cell activity, improve tissue penetration and enable oral administration. Early inhibitors were hampered by limited structural information and suboptimal pharmacokinetics, but advances in crystallography and biophysical assays have revealed binding “hot spots” on PD-L1 and guided the design of dimer-stabilising scaffolds. Macrocyclic peptides and peptidomimetics have also been developed to bridge the potency gap between small molecules and monoclonal antibodies. Preclinical studies demonstrate that select inhibitors can downregulate PD-L1 expression, disrupt its interaction with PD-1 and remodel tumour metabolism, leading to enhanced T-cell infiltration and cytokine release. The evolution of these compounds illustrates the delicate balance between affinity, specificity and drug-like properties, marking a shift towards orally deliverable checkpoint modulators with potential applications across solid tumours and haematological malignancies.

Research from Nature Portfolio

Systematic in vitro characterisation of PD-L1 small molecule inhibitors has provided comprehensive activity and toxicity profiles for prominent BMS-derived compounds and macrocyclic peptides. Detailed biochemical assays confirmed that BMS-103 and BMS-142 engage PD-L1 with high potency, yet revealed that acute cytotoxicity can compromise their immunostimulatory capacity. In contrast, a macrocyclic peptide analogue exhibited favourable cell-based activation and drug-like properties, underscoring the utility of cyclic scaffolds in bridging potency and safety. These findings establish a rigorous experimental benchmark for evaluating next-generation checkpoint inhibitors and inform structure-activity relationships that can guide medicinal chemistry optimisation.

Small Molecule Inhibitors in Cancer Immunotherapy publication trend

The graph below shows the total number of articles in small molecule inhibitors in cancer immunotherapy across all publications each year (not limited to Nature Index journals).

Technical terms

PD-1: Programmed cell death protein 1, an inhibitory receptor on T cells that downregulates immune responses upon binding to its ligands.

PD-L1: Programmed death-ligand 1, a cell-surface protein expressed by tumour and immune cells that interacts with PD-1 to suppress T-cell activity.

Immune checkpoint: A regulatory pathway in the immune system that maintains self-tolerance and limits tissue damage but can be co-opted by tumours to evade detection.

Small-molecule inhibitor: A low-molecular-weight compound designed to selectively bind and modulate the activity of a biological target, often with oral bioavailability.

Macrocyclic peptide: A cyclic, peptide-based compound whose constrained ring structure enhances binding affinity, specificity and metabolic stability compared to linear peptides.

References

1. Comprehensive in vitro characterization of PD-L1 small molecule inhibitors. Scientific Reports (2019).
2. Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma. Cell Death & Disease (2024).
3. Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1). Oncotarget (2016).
4. Development of the Inhibitors That Target the PD-1/PD-L1 Interaction—A Brief Look at Progress on Small Molecules, Peptides and Macrocycles. Molecules (2019).