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.
Applications
- Generation of small molecule immune checkpoint inhibitors against PD-1 by in silico screening
- Binding affinity evaluation and characterization of identified small molecule inhibitors in vitro and in vivo
Advantages
- Cost effective computational identification of small molecule inhibitors of PD-1
- More accessible cancer treatment alternatives
Stage of Development
Research – in vitro
Publications
Tang S and Kim PS. A High-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery. Proc. Natl. Acad. Sci. USA 116(49):24500-24506 (2019)
U.S. Patent No. 10,684,287
Related Web Links
https://peterkimlab.stanford.edu
Keywords
PD-1, PD-L1, crystal structure, small molecule inhibitor
Technology Reference
Chan Zuckerberg CZB-139S, Stanford S19-403
