Nonsymmetrically Substituted 1,1′-Biphenyl-Based Small Molecule Inhibitors of the PD-1/PD-L1 Interaction

Therapeutic antibodies directed against either programmed
cell
death-1 protein (PD-1) or its ligand PD-L1 have demonstrated efficacy
in the treatment of various cancers. In contrast with antibodies,
small molecules have the potential for increased tissue penetration;
better pharmacology; and therefore, improved antitumor activity. A
series of nonsymmetric C2 inhibitors were synthesized and evaluated
for PD-1/PD-L1 interaction inhibition. These compounds induced PD-L1
dimerization and effectively blocked PD-L1/PD-1 interaction in a homogeneous
time-resolved fluorescence (HTRF) assay with most inhibitors exhibiting
IC50 values in the single-digit nM range and below. Their
high inhibitory potency was also demonstrated in a cell-based coculture
PD-1 signaling assay where 2 exhibited an EC50 inhibitory activity of 21.8 nM, which approached that of the PD-L1
antibody durvalumab (EC50 = 0.3–1.8 nM). Structural
insight into how these inhibitors interact with PD-L1 was gained by
using NMR and X-ray cocrystal structure studies. These data support
further preclinical evaluation of these compounds as antibody alternatives.