1. Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors
- Author
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Linda Cerofolini, Gerolama Condorelli, Giovanna Polcaro, Daniela Arosio, Vincenzo Maria D'Amore, Stefano Pepe, Riccardo Scaglia, Marco Fragai, E. Novellino, Giulia Assoni, Luciana Marinelli, Pasquale Russomanno, Stefano Giuntini, Jussara Amato, Diego Brancaccio, Francesco Sabbatino, Marianna Falzoni, Valeria La Pietra, Greta Donati, Paolo Orlando, Pierfausto Seneci, Cristina Quintavalle, Martina Pedrini, Bruno Pagano, Russomanno, P., Assoni, G., Amato, J., D'Amore, V. M., Scaglia, R., Brancaccio, D., Pedrini, M., Polcaro, G., La Pietra, V., Orlando, P., Falzoni, M., Cerofolini, L., Giuntini, S., Fragai, M., Pagano, B., Donati, G., Novellino, E., Quintavalle, C., Condorelli, G., Sabbatino, F., Seneci, P., Arosio, D., Pepe, S., and Marinelli, L.
- Subjects
Models, Molecular ,medicine.drug_class ,Immune Checkpoint Inhibitor ,B7-H1 Antigen ,Calorimetry, Differential Scanning ,Cell Line, Tumor ,Coculture Techniques ,Humans ,Immune Checkpoint Inhibitors ,Neoplasms ,Small Molecule Libraries ,Structure-Activity Relationship ,Triazines ,Calorimetry ,Monoclonal antibody ,Differential Scanning ,Peripheral blood mononuclear cell ,PD-1/PD-L1 ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Small Molecule Librarie ,Models ,PD-L1 ,Drug Discovery ,medicine ,Cytotoxicity ,Coculture Technique ,immune checkpoint ,030304 developmental biology ,0303 health sciences ,Tumor ,biology ,Chemistry ,Molecular ,Small molecule ,3. Good health ,Triazine ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Molecular Medicine ,Neoplasm ,Human - 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.
- Published
- 2021