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 γrelease 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 / 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.; Marinelli, L.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:21(2021), 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
Russomanno P.;Amato J.;D'Amore V. M.;Brancaccio D.;La Pietra V.;Orlando P.;Giuntini S.;Pagano B.;Donati G.;Novellino E.;Quintavalle C.;Condorelli G.;Sabbatino F.;Marinelli L.
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 γrelease 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
