A METHOD OF IDENTIFYING SMALL MOLECULE INHIBITORS FOR PD-1

Researchers at Stanford, funded in part by the Chan Zuckerberg Biohub, have generated a crystal structure for human PD-1 in complex with one of its ligands, PD-L2, for use in small molecule inhibitor design.

Immune checkpoint inhibition of programmed death 1 (PD-1) and its ligand 1 (PD-L1) by monoclonal antibodies (mAbs) has dramatically increased patient survival in many cancer types. While mAbs are clinically beneficial, there is still a need for other small molecule immune checkpoint inhibitors of PD-1. Unfortunately, previous attempts to develop PD-1 small molecule inhibitors have been unsuccessful, due to both the natural structure of PD-1 and the small cavity formed after ligand binding. The development of PD-1 small molecule inhibitors will provide cheaper and more accessible cancer treatment alternatives.

Stage of Research
The inventors performed deep mutational scanning of several loops within human PD-1 and identified a triple mutant with markedly increased affinity for the ligand PD-L2. Crystal structures of the triple mutant alone and in complex with PD-L2 revealed the formation of a small cavity upon ligand association. This pocket provides an attractive impetus for the future rational design, identification and synthesis of small molecules for PD-1 immune checkpoint inhibition.

Stage of Development
Research – in vitro