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Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Nov 11; Vol. 64 (21), pp. 16020-16045. Date of Electronic Publication: 2021 Oct 20. - Publication Year :
- 2021
-
Abstract
- The inhibition of the PD-1/PD-L1 axis by monoclonal antibodies has achieved remarkable success in treating a growing number of cancers. However, a novel class of small organic molecules, with BMS-202 ( 1 ) as the lead, is emerging as direct PD-L1 inhibitors. Herein, we report a series of 2,4,6-tri- and 2,4-disubstituted 1,3,5-triazines, which were synthesized and assayed for their PD-L1 binding by NMR and homogeneous time-resolved fluorescence. Among them, compound 10 demonstrated to strongly bind with the PD-L1 protein and challenged it in a co-culture of PD-L1 expressing cancer cells (PC9 and HCC827 cells) and peripheral blood mononuclear cells enhanced antitumor immune activity of the latter. Compound 10 significantly increased interferon γ release and apoptotic induction of cancer cells, with low cytotoxicity in healthy cells when compared to 1 , thus paving the way for subsequent preclinical optimization and medical applications.
- Subjects :
- Calorimetry, Differential Scanning
Cell Line, Tumor
Coculture Techniques
Humans
Immune Checkpoint Inhibitors chemistry
Models, Molecular
Small Molecule Libraries chemistry
Structure-Activity Relationship
Triazines chemistry
B7-H1 Antigen antagonists & inhibitors
Immune Checkpoint Inhibitors pharmacology
Neoplasms immunology
Neoplasms pathology
Small Molecule Libraries pharmacology
Triazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34670084
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c01409