Abstract
Cancer immunotherapy based on antibodies targeting the immune checkpoint PD-1/PD-L1 pathway has seen unprecedented clinical responses and constitutes the new paradigm in cancer therapy. The antibody-based immunotherapies have several limitations such as high production cost of the antibodies or their long half-life. Small-molecule inhibitors of the PD-1/PD-L1 interaction have been highly anticipated as a promising alternative or complementary therapeutic to the monoclonal antibodies (mAbs). Currently, the field of developing anti-PD-1/PD-L1 small-molecule inhibitors is intensively explored. In this paper, we review anti-PD-1/PD-L1 small-molecule and peptide-based inhibitors and discuss recent structural and preclinical/clinical aspects of their development. Discovery of the therapeutics based on small-molecule inhibitors of the PD-1/PD-L1 interaction represents a promising but challenging perspective in cancer treatment.
Highlights
The programmed cell death protein 1 (PD-1, known as CD279) belongs to the family of immune checkpoint proteins expressed on the surfaces of various immune cells, including T-cells, B-cells, monocytes, natural killer cells, and dendritic cells [1,2]
We describe structure-activity relationship (SAR) aspects of the currently known active compounds and their cocrystal structures
Optimization of the structure mostly focused on the molecules’ amino acid side chains. This led to the discovery of tripeptide peptidomimetics with higher activities, especially when the lysine residue was introduced into the side chain, which led to an increase of the mouse splenocyte proliferation assays (MSPA) rates up to 87% [46]
Summary
The programmed cell death protein 1 (PD-1, known as CD279) belongs to the family of immune checkpoint proteins expressed on the surfaces of various immune cells, including T-cells, B-cells, monocytes, natural killer cells, and dendritic cells [1,2]. X-ray structures of the complexes between the peptides and PD-L1 clearly indicated that their pharmacophores differ from those already known for small-molecule compounds [41,42,43] This may provide an alternative scaffold and extra fragments for the design of new small-molecule antagonists of the PD-1/PD-L1 pathway [38,39,44] (See Section 2.2, Figure 17). The SAR modifications of the macrocyclic peptides indicated that the compounds with a glycol chain are superior to those with an aliphatic closure [28,33,48] These modifications were followed by proposing macrocyclic inhibitors 11, 12 indicating splenocyte proliferation rates of 95 and 94% in the MSPA assay (Figure 7). The highest splenocyte proliferation in the presence of recombinant mouse PD-L1/PD-L2 (up to 92%) was assigned to the small molecule 21 shown in Figure 11 (21) [52,58]
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