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 gamma 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.

Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors / P. Russomanno, G. Assoni, J. Amato, V.M. D'Amore, R. Scaglia, D. Brancaccio, M. Pedrini, G. Polcaro, V. La Pietra, P. Orlando, M. Falzoni, L. Cerofolini, S. Giuntini, M. Fragai, B. Pagano, G. Donati, E. Novellino, C. Quintavalle, G. Condorelli, F. Sabbatino, P. Seneci, D. Arosio, S. Pepe, L. Marinelli. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:21(2021 Nov 11), pp. 16020-16045. [10.1021/acs.jmedchem.1c01409]

Interfering with the Tumor-Immune Interface: Making Way for Triazine-Based Small Molecules as Novel PD-L1 Inhibitors

M. Pedrini;P. Orlando;P. Seneci
;
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 gamma 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.
B7-H1 Antigen; Calorimetry, Differential Scanning; Cell Line, Tumor; Coculture Techniques; Humans; Immune Checkpoint Inhibitors; Models, Molecular; Neoplasms; Small Molecule Libraries; Structure-Activity Relationship; Triazines
Settore CHIM/06 - Chimica Organica
11-nov-2021
ott-2021
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/944068
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