Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 13, Pages 5857-5867Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00293
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Funding
- Marie Curie FP7 Reintegration Grant within the 7th European Community Framework Programme
- National Science Centre [UMO-2011/01/D/NZ1/01169, UMO-2012/07/E/NZ1/01907, UMO-2015/19/N/STS/00347, UMO-2016/20/T/NZ1/00519]
- European Union [POIG.02.01.00-12-064/08, POIG.02.01.00-12-167/08]
- European Regional Development Fund [POIG.02.01.00-12-167/08, POIG.02.01.00-12-023/08]
- National Centre of Science [UMO-2015/19/D/NZ1/02009]
- Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, which is a partner of the Leading National Research Centre (KNOW) - Ministry of Science and Higher Education
- [UMO-2012/06/A/STS/00224]
- [UMO-2014/12/W/NZ1/00457]
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Blockade of the PD-1/PD-L1 immune checkpoint pathway with monoclonal antibodies has provided significant advances in cancer treatment. The antibody-based immunotherapies carry a number of disadvantages such as the high cost of the antibodies, their limited half-life, and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors that could overcome these drawbacks is slow because of the incomplete structural information for this pathway. The first chemical PD-1/PD-L1 inhibitors have been recently disclosed by Bristol-Myers Squibb. Here we present NMR and X-ray characterization for the two classes of these inhibitors. The X-ray structures of the PD-L1/inhibitor complexes reveal one inhibitor molecule located at the center of the PD-L1 homodimer, filling a deep hydrophobic channel-like pocket between two PD-L1 molecules. Derivatives of (2-methyl-3-biphenylyl)methanol exhibit the structures capped on one side of the channel, whereas the compounds based on [3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]methanol induce an enlarged interaction interface that results in the open face-back tunnel through the PD-L1 dimer.
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