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

Autor:	Przemyslaw Grudnik, Lukasz Skalniak, Bogdan Musielak, Katarzyna Magiera, Grzegorz Dubin, Tad A. Holak, Krzysztof M. Zak, Ricarda Törner, Alexander Dömling, Katarzyna Guzik
Přispěvatelé:	Drug Design, Medicinal Chemistry and Bioanalysis (MCB)
Rok vydání:	2017
Předmět:	0301 basic medicine 4 benzodioxin 6 yl) 2 methylphenyl]methanol crystallization medicine.medical_treatment 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 hydroxy 5 methylbenzaldehyde 2 6 dimethoxy 4 [(2 methyl 3 phenylphenyl)methoxy]benzaldehyde Programmed Cell Death 1 Receptor 6 dimethoxy 4 [(2 methyl 3 phenylphenyl)methoxy]phenyl]methyl]amino] 3 methylbutan 1 ol hydrochloride 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 IC50 X ray analysis Crystallography X-Ray B7-H1 Antigen 1 [[3 bromo 4 [(2 methyl 3 phenylphenyl)methoxy]phenyl]methyl]piperidine 2 carboxylic acid 0302 clinical medicine Protein structure Cancer immunotherapy 6 dimethoxy 4 [(2 methyl 3 phenylphenyl)methoxy]benzaldehyde 4 benzodioxin 6 yl) 2methylphenyl]methoxy] 2 Drug Discovery Protein Interaction Maps drug determination 3 [4 chloro 5 [[3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 formylphenoxymethyl]benzonitrile dimerization biology 4 [[[4 [[3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2methylphenyl]methoxy] 2 5 difluorophenyl]methyl]amino] 3 hydroxybutanoic acid hydrochloride Chemistry heteronuclear multiple quantum coherence article Nuclear magnetic resonance spectroscopy 5 difluorobenzaldehyde protein function Ligand (biochemistry) Small molecule unclassified drug 2 methoxy 6 [(2 methyl 3 phenylphenyl)methoxy]pyridine 3 carbaldehyde Molecular Docking Simulation 030220 oncology & carcinogenesis [3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2 methylphenyl]methanol Molecular Medicine [3 (2 medicine.drug_class Stereochemistry 3 dihydro 1 2 [[[2 [(3 cyanophenyl)methoxy] 4 [[3 (2 4 [[3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 5 difluorobenzaldehyde 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 hydroxybenzaldehyde 3 [4 chloro 5 [[3 (2 Monoclonal antibody oligomerization 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 5 methylphenyl] methyl]amino] 3 hydroxypropanoic acid hydrochloride Small Molecule Libraries 3 [5 [[3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 formyl 4 methylphenoxymethyl]benzonitrile 03 medical and health sciences 3 bromo 4 [(2 methyl 3 phenylphenyl)methoxy]benzaldehyde PD-L1 n [2 [[[2 methoxy 6 [(2 methyl 3 phenylphenyl)methoxy]pyridin 3 yl]methyl]amino]ethyl]acetamide hydrochloride 5 chloro 4 [[3 (2 medicine 3 [5 [[3 (2 (2 methyl 3 biphenylyl)methanol Humans 2 [[[2 human protein interaction protein structure protein expression hydrophobicity nuclear magnetic resonance spectroscopy 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 4 benzodioxin 6 yl) 2 methylphenyl]methoxy]phenyl] methyl] 4 hydroxypyrrolidine 2 carboxylic acid hydrochloride cancer immunotherapy 2 [[[2 6 dimethoxy 4 [(2 methyl 3 phenylphenyl)methoxy]phenyl]methyl]amino] 3 methylbutan 1 ol hydrochloride 5 difluorophenyl]methyl]amino] 3 hydroxybutanoic acid hydrochloride 1 [[5 chloro 2 [(3 cyanophenyl)methoxy] 4 [[3 (2 Immune checkpoint 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 formylphenoxymethyl]benzonitrile programmed death 1 ligand 1 drug structure 030104 developmental biology 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 formyl 4 methylphenoxymethyl]benzonitrile protein inhibitor 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 5 chloro 4 [[3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 hydroxybenzaldehyde 4 [[3 (2 biology.protein drug synthesis immunomodulating agent 4 [[[4 [[3 (2 Protein Multimerization 4 [[3 (2 3 dihydro 1 4 benzodioxin 6 yl) 2 methylphenyl]methoxy] 2 hydroxy 5 methylbenzaldehyde
Zdroj:	Journal of Medicinal Chemistry, 60(13), 5857-5867. AMER CHEMICAL SOC
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::625d97b965a27503a0c562a8cfaf459d https://pubmed.ncbi.nlm.nih.gov/28613862 Zobrazit plný text záznamu