4.7 Article

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

Journal

JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 21, Pages 16020-16045

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01409

Keywords

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Funding

  1. Italian Ministry of Education, University, and Research (MIUR) [2017PHRC8X 004]
  2. Regione Campania. POR Campania FESR 2014/2020 [B61G18000470007]
  3. H2020-MSCA-RISE-2019 cONCReTE [872391]
  4. H2020-MSCA-RISE-2019 PRISAR2 [872860]
  5. MSCA-ITN-ETN CAST [857894]
  6. MSCA-ITNETN PAVE [861190]
  7. Regione Campania Project PO FESR 2014-2020-SATIN

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A series of novel small organic molecules have been identified for their strong binding affinity with the PD-L1 protein, demonstrating the potential to challenge tumor cells in co-culture experiments without significant harm to healthy cells.
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.

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