Bioactive Macrocyclic Inhibitors of the PD‐1/PD‐L1 Immune Checkpoint

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. Trennender Ring: Makrocyclische Peptid‐Inhibitoren können den PD‐1/PD‐L1‐Pfad blockieren, indem sie direkt an PD‐L1 binden und, ähnlich wie Anti‐PD‐L1‐Antikörper, die Funktion von T‐Zellen wiederherstellen. Strukturen der Grenzfläche zwischen Makrocyclus und PD‐L1 bilden die Grundlage für den Entwurf von niedermolekularen Inhibitoren mit Antitumoreigenschaften.