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- Title
Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint.
- Authors
Magiera‐Mularz, Katarzyna; Skalniak, Lukasz; Zak, Krzysztof M.; Musielak, Bogdan; Rudzinska‐Szostak, Ewa; Berlicki, Łukasz; Kocik, Justyna; Grudnik, Przemyslaw; Sala, Dominik; Zarganes‐Tzitzikas, Tryfon; Shaabani, Shabnam; Dömling, Alexander; Dubin, Grzegorz; Holak, Tad A.
- Abstract
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.
- Subjects
MONOCLONAL antibodies; TUMOR prevention; PEPTIDES; MACROCYCLIC compounds; IMMUNOTHERAPY
- Publication
Angewandte Chemie, 2017, Vol 129, Issue 44, p13920
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201707707