Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell Death-Ligand 1 Interaction

With the successful clinical application
of anti-programmed cell
death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) monoclonal antibodies
(mAb), targeting the PD-1/PD-L1 interaction has become a promising
method for the discovery of cancer therapy. Due to the inherent limitations
of antibodies, it is necessary to search for small-molecule inhibitors
against the PD-1/PD-L1 axis. We report the design, synthesis, and
evaluation in vitro and in vivo of
a series of novel biphenyl pyridines as the inhibitors of PD-1/PD-L1.
2-(((2-Methoxy-6-(2-methyl-[1,1′-biphenyl]-3-yl)­pyridin-3-yl)­methyl)­amino)­ethan-1-ol
(24) was found to inhibit the PD-1/PD-L1 interaction
with an IC50 value of 3.8 ± 0.3 nM and enhance the
killing activity of tumor cells by immune cells. Compound 24 displays great pharmacokinetics (oral bioavailability of 22%) and
significant in vivo antitumor activity in a CT26
mouse model. Flow cytometry and immunohistochemistry data indicated
that compound 24 activates the immune activity in tumors.
These results suggest that compound 24 is a promising
small-molecule inhibitor against the PD-1/PD-L1 axis and merits further
development.