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

Magiera-Mularz, K., Skalniak, L., Zak, K. M., Musielak, B., Rudzinska-Szostak, E., Berlicki, L., et al. (2017). Bioactive Macrocyclic Inhibitors of the PD-1/PD-L1 Immune Checkpoint. Angewandte Chemie International Edition, 56(44), 13732-13735. doi:10.1002/anie.201707707.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-9680-D Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-9681-B
Genre: Journal Article

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 Creators:
Magiera-Mularz, Katarzyna1, Author
Skalniak, Lukasz1, Author
Zak, Krzysztof M.1, Author
Musielak, Bogdan1, Author
Rudzinska-Szostak, Ewa1, Author
Berlicki, Lukasz1, Author
Kocik, Justyna1, Author
Grudnik, Przemyslaw1, Author
Sala, Dominik1, Author
Zarganes-Tzitzikas, Tryfon1, Author
Shaabani, Shabnam1, Author
Doemling, Alexander1, Author
Dubin, Grzegorz1, Author
Holak, Tad A.2, Author              
Affiliations:
1external, ou_persistent22              
2Holak, Tad / NMR Spectroscopy, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565154              

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Free keywords: CANCER-IMMUNOTHERAPY; MONOCLONAL-ANTIBODIES; BLOCKADE; THERAPY; FUTUREChemistry; antitumor agents; inhibitors; peptides; PD-1/PD-L1; protein-protein interactions;
 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.

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Language(s): eng - English
 Dates: 2017
 Publication Status: Published in print
 Pages: 4
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000413314800033
DOI: 10.1002/anie.201707707
 Degree: -

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Title: Angewandte Chemie International Edition
  Other : Angew. Chem., Int. Ed.
  Other : Angew. Chem. Int. Ed.
  Other : Angewandte Chemie, International Edition
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Weinheim : Wiley-VCH
Pages: - Volume / Issue: 56 (44) Sequence Number: - Start / End Page: 13732 - 13735 Identifier: ISSN: 1433-7851
CoNE: https://pure.mpg.de/cone/journals/resource/1433-7851