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Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction
- Source :
- Bioorganic & Medicinal Chemistry Letters. 29:2464-2467
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- The development of small molecule inhibitors of PD-1/PD-L1 is eagerly anticipated for treatment of cancer. We focused on the symmetry of the ternary complex structure of reported small molecule ligands and hPD-L1 homodimers, and designed partially- or fully-symmetric compounds for more potent inhibitors. The design of the new compounds was guided by our hypothesis that the designed symmetric compound would induce a flip of sidechain of ATyr56 protein residue to form a new cavity. The designed compound 4 exhibited substantially increased binding affinity to hPD-L1, as well as PD-1/PD-L1 inhibitory activity in physiological conditions. Compound 4 also showed a dose-dependent increase in IFN-γ secretion levels in a mixed lymphocyte reaction assay. These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers.
- Subjects :
- Stereochemistry
Programmed Cell Death 1 Receptor
Clinical Biochemistry
Pharmaceutical Science
Ligands
Biochemistry
Antibodies
B7-H1 Antigen
Small Molecule Libraries
Interferon-gamma
Residue (chemistry)
PD-L1
Drug Discovery
Humans
Surface plasmon resonance
Molecular Biology
Ternary complex
biology
Chemistry
Organic Chemistry
Dendritic Cells
Surface Plasmon Resonance
Mixed lymphocyte reaction
Ligand (biochemistry)
Small molecule
Flip
Drug Design
biology.protein
Molecular Medicine
Dimerization
Protein Binding
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....1f7621b57dcb425686500ccc5ebc1134