A METHOD OF IDENTIFYING SMALL MOLECULE INHIBITORS FOR PD-1

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

Patent Information:
For Information, Contact:
CZBiohub Admin
Inteum Hosted Admin
CZ Biohub
ip@czbiohub.org
Inventors:
Shaogeng Tang
Peter Kim
Keywords:
Crystal Structure
PD-1
PD-L1
Small Molecule Inhibitor