Magiera-Mularz, K.; Skalniak, L.; Zak, K.M.; Musielak, B.; Rudzinska-Szostak, E.; Kocik, J.; Grudnik, P.; Sala, D.; Zarganes-Tzitzikas, T.; Shaabani, S.; Domling, A.; Dubin, G.; Holak, T.A.: Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint. Angewandte Chemie - International Edition 56 (2017), p. 13732-13735
10.1002/anie.201707707
Open Access Version (externer Anbieter)
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.