Small-Molecule Inhibitors of the Programmed Cell Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) Interaction via Transiently Induced Protein States and Dimerization of PD-L1

Blockade
of the PD-1/PD-L1 immune checkpoint pathway with monoclonal
antibodies has provided significant advances in cancer treatment.
The antibody-based immunotherapies carry a number of disadvantages
such as the high cost of the antibodies, their limited half-life,
and immunogenicity. Development of small-molecule PD-1/PD-L1 inhibitors
that could overcome these drawbacks is slow because of the incomplete
structural information for this pathway. The first chemical PD-1/PD-L1
inhibitors have been recently disclosed by Bristol-Myers Squibb. Here
we present NMR and X-ray characterization for the two classes of these
inhibitors. The X-ray structures of the PD-L1/inhibitor complexes
reveal one inhibitor molecule located at the center of the PD-L1 homodimer,
filling a deep hydrophobic channel-like pocket between two PD-L1 molecules.
Derivatives of (2-methyl-3-biphenylyl)­methanol exhibit the structures
capped on one side of the channel, whereas the compounds based on
[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-methylphenyl]­methanol
induce an enlarged interaction interface that results in the open
“face-back” tunnel through the PD-L1 dimer.