Research Papers:

Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells

Lukasz Skalniak, Krzysztof M. Zak, Katarzyna Guzik, Katarzyna Magiera, Bogdan Musielak, Magdalena Pachota, Bozena Szelazek, Justyna Kocik, Przemyslaw Grudnik, Marcin Tomala, Sylwia Krzanik, Krzysztof Pyrc, Alexander Dömling, Grzegorz Dubin & Tad A. Holak _

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Oncotarget. 2017; 8:72167-72181. https://doi.org/10.18632/oncotarget.20050

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Lukasz Skalniak1,*, Krzysztof M. Zak2,3,*, Katarzyna Guzik1, Katarzyna Magiera1, Bogdan Musielak1, Magdalena Pachota2,3, Bozena Szelazek2,3, Justyna Kocik1, Przemyslaw Grudnik2,3, Marcin Tomala1, Sylwia Krzanik2,3, Krzysztof Pyrc2,3, Alexander Dömling4, Grzegorz Dubin2,3 and Tad A. Holak1

1Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, 30-060 Krakow, Poland

2Malopolska Centre of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland

3Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland

4Department of Drug Design, University of Groningen, 9713 AV Groningen, The Netherlands

*These authors contributed equally to this work

Correspondence to:

Tad A. Holak, email: holak@chemia.uj.edu.pl

Grzegorz Dubin, email: grzegorz.dubin@uj.edu.pl

Keywords: PD-1, PD-L1, small-molecules, immune checkpoint blockade, inhibitor

Received: June 14, 2017     Accepted: July 25, 2017     Published: August 07, 2017


Antibodies targeting the PD-1/PD-L1 immune checkpoint achieved spectacular success in anticancer therapy in the recent years. In contrast, no small molecules with cellular activity have been reported so far. Here we provide evidence that small molecules are capable of alleviating the PD-1/PD-L1 immune checkpoint-mediated exhaustion of Jurkat T-lymphocytes. The two optimized small-molecule inhibitors of the PD-1/PD-L1 interaction, BMS-1001 and BMS-1166, developed by Bristol-Myers Squibb, bind to human PD-L1 and block its interaction with PD-1, when tested on isolated proteins. The compounds present low toxicity towards tested cell lines and block the interaction of soluble PD-L1 with the cell surface-expressed PD-1. As a result, BMS-1001 and BMS-1166 alleviate the inhibitory effect of the soluble PD-L1 on the T-cell receptor-mediated activation of T-lymphocytes. Moreover, the compounds were effective in attenuating the inhibitory effect of the cell surface-associated PD-L1. We also determined the X-ray structures of the complexes of BMS-1001 and BMS-1166 with PD-L1, which revealed features that may be responsible for increased potency of the compounds compared to their predecessors. Further development may lead to the design of an anticancer therapy based on the orally delivered immune checkpoint inhibition.

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