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

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

  • J Med Chem. 2021 Nov 11;64(21):16020-16045. doi: 10.1021/acs.jmedchem.1c01409.
Pasquale Russomanno 1,  Giulia Assoni 2 3,  Jussara Amato 1,  Vincenzo Maria D'Amore 1,  Riccardo Scaglia 3,  Diego Brancaccio 1,  Martina Pedrini 3,  Giovanna Polcaro 4,  Valeria La Pietra 1,  Paolo Orlando 3,  Marianna Falzoni 3,  Linda Cerofolini 5,  Stefano Giuntini 5,  Marco Fragai 5,  Bruno Pagano 1,  Greta Donati 1,  Ettore Novellino 6,  Cristina Quintavalle 7,  Gerolama Condorelli 7 8,  Francesco Sabbatino 4,  Pierfausto Seneci 3,  Daniela Arosio 9,  Stefano Pepe 4,  Luciana Marinelli 1
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 49, Napoli 80131, Italy.
  • 2 Department of Cellular, Computational and Integrative Biology, (CIBIO), Università degli Studi di Trento, Via Sommarive 9, Povo I-38123, Trento, Italy.
  • 3 Chemistry Department, Università degli Studi di Milano, Via C. Golgi 19, Milan 20133, Italy.
  • 4 Dipartimento di Medicina e Chirurgia, Ospedale "San Giovanni di Dio e Ruggi d'Aragona", Università di Salerno, Salerno 84131, Italy.
  • 5 Centro di Risonanza Magnetica, CERM, Università di Firenze, Firenze 50019, Italy.
  • 6 Università Cattolica del Sacro Cuore, Rome 00168, Italy.
  • 7 Department of Molecular Medicine and Medical Biotechnology, "Federico II" University, Naples, Italy; Institute for Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Naples 80131, Italy.
  • 8 Department of Molecular Medicine and Medical Biotechnology, "Federico II" University, Naples 80131, Italy.
  • 9 Istituto di Scienze e Tecnologie Chimiche "Giulio Natta" (SCITEC), Consiglio Nazionale delle Ricerche (CNR), Via C. Golgi 19, Milan 20133, Italy.
PMID: 34670084 DOI: 10.1021/acs.jmedchem.1c01409
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.

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