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

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.