Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 56, Issue 44, Pages 13732-13735Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201707707
Keywords
antitumor agents; inhibitors; peptides; PD-1/PD-L1; protein-protein interactions
Categories
Funding
- National Science Centre, Poland [UMO-2012/06/A/ST5/00224, UMO-2014/12/W/NZ1/00457, UMO-2016/21/D/NZ7/00596, UMO-2012/07/E/NZ1/01907, UMO-2015/19/D/NZ1/02009, UMO-2016/20/T/NZ1/00519]
- EU European Regional Development Fund
- Marie Curie FP7-Reintegration-Grant within the seventh European Community Framework Programme
- Polish Ministry of Science and Higher Education
- NIH [2R01GM097082-05]
- COFUND [665250]
- KWF grant [10504]
- European Union [POIG.02.01.00-12-064/08, POIG.02.01.00-12-167/08]
- European Regional Development Fund in the framework of the Polish Innovation Economy Operational Program [POIG.02.01.00-58212-023/08]
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Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types, whereas the development of small molecules targeting immune checkpoints lags far behind. We characterized two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclic compounds act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide a rationale for the checkpoint inhibition by these small molecules, and a description of their small molecule/PD-L1 interfaces provides a blueprint for the design of small-molecule inhibitors of the PD-1/PD-L1 pathway.
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