Di-bromo-Based Small-Molecule Inhibitors of the PD-1/PD-L1 Immune Checkpoint

Immune checkpoint blockade is one
of the most promising strategies
of cancer immunotherapy. However, unlike classical targeted therapies,
it is currently solely based on expensive monoclonal antibodies, which
often inflict immune-related adverse events. Herein, we propose a
novel small-molecule inhibitor targeted at the most clinically relevant
immune checkpoint, PD-1/PD-L1. The compound is capable of disrupting
the PD-1/PD-L1 complex by antagonizing PD-L1 and, therefore, restores
activation of T cells similarly to the antibodies, while being cheap
in production and possibly nonimmunogenic. The final compound is significantly
smaller than others reported in the literature while being nontoxic
to cells even at high concentrations. The scaffold was designed using
a structure–activity relationship screening cascade based on
a new antagonist-induced dissociation NMR assay, called the weak-AIDA-NMR.
Weak-AIDA-NMR finds true inhibitors, as opposed to only binders to
the target protein, in early steps of lead compound development, and
this process makes it less time and cost consuming.