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PDBsum entry 5n2d
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References listed in PDB file
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Key reference
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Title
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Small-Molecule inhibitors of the programmed cell death-1/programmed death-Ligand 1 (pd-1/pd-L1) interaction via transiently induced protein states and dimerization of pd-L1.
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Authors
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K.Guzik,
K.M.Zak,
P.Grudnik,
K.Magiera,
B.Musielak,
R.Törner,
L.Skalniak,
A.Dömling,
G.Dubin,
T.A.Holak.
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Ref.
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J Med Chem, 2017,
60,
5857-5867.
[DOI no: ]
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PubMed id
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Abstract
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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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