Bioactive Macrocyclic Inhibitors of the PD‐1/PD‐L1 Immune Checkpoint. (26th September 2017)

• Record Type: Journal Article
• 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.
• Is Part Of: Angewandte Chemie. Volume 129:Number 44(2017)
• Page Start: 13920
• Page End: 13923
• Publication Date: 2017-09-26
• Subjects: Tumortherapeutika -- Inhibitoren -- Peptide -- PD-1/PD-L1 -- Protein-Protein-Wechselwirkungen; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201707707
• Languages: English
• ISSNs: 0044-8249

Abstract

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.