Discovery of Small-Molecule Inhibitors of the PD-1/PD-L1 Axis That Promote PD-L1 Internalization and Degradation

Several
monoclonal antibodies targeting the programmed cell death-1/programmed
cell death-ligand 1 (PD-1/PD-L1) pathway have been used successfully
in anticancer immunotherapy. Inherent limitations of antibody-based
therapies remain, however, and alternative small-molecule inhibitors
that can block the PD-1/PD-L1 axis are urgent needed. Herein, we report
the discovery of compound 17 as a bifunctional inhibitor
of PD-1/PD-L1 interactions. 17 inhibits PD-1/PD-L1 interactions
and promotes dimerization, internalization, and degradation of PD-L1. 17 promotes cell-surface PD-L1 internalized into the cytosol
and induces the degradation of PD-L1 in tumor cells through a lysosome-dependent
pathway. Furthermore, 17 suppresses tumor growth in vivo by activating antitumor immunity. These results
demonstrate that 17 targets the PD-1/PD-L1 axis and induces
PD-L1 degradation.