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Bioactive Macrocyclic Inhibitors of the PD‐1/PD‐L1 Immune Checkpoint
Author(s) -
MagieraMularz Katarzyna,
Skalniak Lukasz,
Zak Krzysztof M.,
Musielak Bogdan,
RudzinskaSzostak Ewa,
Berlicki Łukasz,
Kocik Justyna,
Grudnik Przemyslaw,
Sala Dominik,
ZarganesTzitzikas Tryfon,
Shaabani Shabnam,
Dömling Alexander,
Dubin Grzegorz,
Holak Tad A.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201707707
Subject(s) - small molecule , pd l1 , monoclonal antibody , immune checkpoint , chemistry , blockade , immune system , antibody , palladium , cancer research , immunotherapy , stereochemistry , biochemistry , biology , immunology , receptor , catalysis
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.