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Publication Abstract from PubMed

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. Here we characterize two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclics 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 rationales for the checkpoint inhibition by these small molecules and description of their small molecule/PD-L1 interfaces provides a blueprint for design of small-molecule inhibitors of the PD-1/PD-L1 pathway.

Bioactive macrocyclic inhibitors of the PD-1/PD-L1 immune checkpoint.,Magiera-Mularz K, Skalniak L, Zak KM, Musielak B, Rudzinska-Szostak E, Berlicki L, Kocik J, Grudnik P, Sala D, Zizigas-Zarganis T, Shaabani S, Domling A, Dubin G, Holak TA Angew Chem Int Ed Engl. 2017 Sep 7. doi: 10.1002/anie.201707707. PMID:28881104^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.