Structural basis for small molecule targeting of the programmed death ligand 1 (PD-L1)

  • Oncotarget. 2016 May 24;7(21):30323-35. doi: 10.18632/oncotarget.8730.
Krzysztof M Zak  1  2 ,  Przemyslaw Grudnik  2 ,  Katarzyna Guzik  3 ,  Bartosz J Zieba  1  3 ,  Bogdan Musielak  3 ,  Alexander Dömling  4 ,  Grzegorz Dubin  1  2 ,  Tad A Holak  1  3  5
Affiliations
  • 1. Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.
  • 2. Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa, Krakow, Poland.
  • 3. Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Ingardena, Krakow, Poland.
  • 4. Department for Drug Design, University of Groningen, A. Deusinglaan , Groningen, The Netherlands.
  • 5. Max Planck Institute for Biochemistry, Am Klopferspitz, Martinsried, Germany.
PMID: 27083005 DOI: 10.18632/oncotarget.8730
Abstract

Targeting the PD-1/PD-L1 immunologic checkpoint with monoclonal antibodies has provided unprecedented results in Cancer treatment in the recent years. Development of chemical inhibitors for this pathway lags the antibody development because of insufficient structural information. The first nonpeptidic chemical inhibitors that target the PD-1/PD-L1 interaction have only been recently disclosed by Bristol-Myers Squibb. Here, we show that these small-molecule compounds bind directly to PD-L1 and that they potently block PD-1 binding. Structural studies reveal a dimeric protein complex with a single small molecule which stabilizes the dimer thus occluding the PD-1 interaction surface of PD-L1s. The small-molecule interaction "hot spots" on PD-L1 surfaces suggest approaches for the PD-1/PD-L1 antagonist drug discovery.

Keywords
X-ray structure; checkpoint inhibitor; immunotherapy; small molecule.
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