Abstract
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.
Highlights
Tumors can bypass immune surveillance by exploiting immune-escape mechanisms including the induction of an immunosuppressive microenvironment and suppression of effector T cells’ function in the tumor microenvironment [1, 2]
Antigens are presented by antigen-presenting cells (APCs) such as dendritic cells (DCs) as antigenic peptides, which are recognized by the T-cell receptor (TCR; Signal 1) [12]
programmed death-ligand 1 (PD-L1) expressed by cancer cells binds to its receptor Programmed cell death protein 1 (PD-1) located on activated T cells on the tumor sites
Summary
Tumors can bypass immune surveillance by exploiting immune-escape mechanisms including the induction of an immunosuppressive microenvironment and suppression of effector T cells’ function in the tumor microenvironment [1, 2]. Monoclonal antibodies (mAbs) targeting PD-1 (e.g. Cemiplimab, Nivolumab, and Pembrolizumab) or PD-L1 (e.g. Durvalumab, Avelumab, and Atezolizumab) are approved by the United States FDA for the treatment of a series of malignancies [16, 36–38] These mAbs exhibit promising therapeutic effectiveness in clinical studies, restrictions including immune-related adverse effects, immunogenicity, and high costs are imposed for the clinical utilization of antibody-based immune checkpoint inhibitors [15, 17, 39, 40]. PD-L1 expressed by cancer cells binds to its receptor PD-1 located on activated T cells on the tumor sites This interaction triggers inhibitory signals to the T cells and prevents the host immune system from suppressing the growth of tumor [56]. PI3K/Akt signaling pathway blockage further regulates a series of downstream cellular events including the activation of a
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