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
  • 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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