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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

Guzik, K., Zak, K. M., Grudnik, P., Magiera, K., Musielak, B., Törner, R., Skalniak, L., Dömling, A., Dubin, G. & Holak, T. A., 13-Jul-2017, In : Journal of Medicinal Chemistry. 60, 13, p. 5857-5867 11 p.

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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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DOI

  • Katarzyna Guzik
  • Krzysztof M. Zak
  • Przemyslaw Grudnik
  • Katarzyna Magiera
  • Bogdan Musielak
  • Ricarda Törner
  • Lukasz Skalniak
  • Alexander Dömling
  • Grzegorz Dubin
  • Tad A. Holak
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.
Original languageEnglish
Pages (from-to)5857-5867
Number of pages11
JournalJournal of Medicinal Chemistry
Volume60
Issue number13
Publication statusPublished - 13-Jul-2017

    Keywords

  • (2 methyl 3 biphenylyl)methanol, 1 [[3 bromo 4 [(2 methyl 3 phenylphenyl)methoxy]phenyl]methyl]piperidine 2 carboxylic acid, 1 [[5 chloro 2 [(3 cyanophenyl)methoxy] 4 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy]phenyl] methyl] 4 hydroxypyrrolidine 2 carboxylic acid hydrochloride, 2 [[[2 [(3 cyanophenyl)methoxy] 4 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 5 methylphenyl] methyl]amino] 3 hydroxypropanoic acid hydrochloride, 2 [[[2,6 dimethoxy 4 [(2 methyl 3 phenylphenyl)methoxy]phenyl]methyl]amino] 3 methylbutan 1 ol hydrochloride, 2 methoxy 6 [(2 methyl 3 phenylphenyl)methoxy]pyridine 3 carbaldehyde, 2,6 dimethoxy 4 [(2 methyl 3 phenylphenyl)methoxy]benzaldehyde, 3 [4 chloro 5 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 formylphenoxymethyl]benzonitrile, 3 [5 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 formyl 4 methylphenoxymethyl]benzonitrile, 3 bromo 4 [(2 methyl 3 phenylphenyl)methoxy]benzaldehyde, 4 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 hydroxy 5 methylbenzaldehyde, 4 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2,5 difluorobenzaldehyde, 4 [[[4 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2methylphenyl]methoxy] 2,5 difluorophenyl]methyl]amino] 3 hydroxybutanoic acid hydrochloride, 5 chloro 4 [[3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 hydroxybenzaldehyde, [3 (2,3 dihydro 1,4 benzodioxin 6 yl) 2 methylphenyl]methanol, immunomodulating agent, n [2 [[[2 methoxy 6 [(2 methyl 3 phenylphenyl)methoxy]pyridin 3 yl]methyl]amino]ethyl]acetamide hydrochloride, programmed death 1 ligand 1, protein inhibitor, unclassified drug, article, cancer immunotherapy, crystallization, dimerization, drug determination, drug structure, drug synthesis, heteronuclear multiple quantum coherence, human, hydrophobicity, IC50, nuclear magnetic resonance spectroscopy, oligomerization, protein expression, protein function, protein interaction, protein structure, X ray analysis

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