Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

Programmed death-1/programmed death ligand-1 (PD-1/PD-L1) based immunotherapy is a revolutionary cancer therapy with great clinical success. The majority of clinically used PD-1/PD-L1 inhibitors are monoclonal antibodies but their applications are limited due to their poor oral bioavailability and immune-related adverse effects (irAEs). In contrast, several small molecule inhibitors against PD-1/PD-L1 immune checkpoints show promising blockage effects on PD-1/PD-L1 interactions without irAEs. However, proper analytical methods and bioassays are required to effectively screen small molecule derived PD-1/PD-L1 inhibitors. Herein, we summarize the biophysical and biochemical assays currently employed for the measurements of binding capacities, molecular interactions, and blocking effects of small molecule inhibitors on PD-1/PD-L1. In addition, the discovery of natural products based PD-1/PD-L1 antagonists utilizing these screening assays are reviewed. Potential pitfalls for obtaining false leading compounds as PD-1/PD-L1 inhibitors by using certain binding bioassays are also discussed in this review.

Automated summary

PD-1/PD-L1 based immunotherapy has shown great clinical success in cancer treatment, but the use of monoclonal antibodies is limited by poor oral bioavailability and immune-related adverse effects. On the other hand, some small molecule inhibitors provide promising blockage effects without immune-related adverse effects. Proper analytical methods and bioassays are essential for effectively screening small molecule PD-1/PD-L1 inhibitors.