2. Academic Validation
  3. Discovery and Optimization of Small-Molecule Ligands for V-Domain Ig Suppressor of T-Cell Activation (VISTA)

Discovery and Optimization of Small-Molecule Ligands for V-Domain Ig Suppressor of T-Cell Activation (VISTA)

  • J Am Chem Soc. 2020 Sep 23;142(38):16194-16198. doi: 10.1021/jacs.0c07276.
Moustafa T Gabr 1 2,  Sanjiv S Gambhir 1 2 3
Affiliations

Affiliations

  • 1 Bio-X Program and Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California 94305, United States.
  • 2 Department of Radiology, Stanford University, Stanford, California 94305, United States.
  • 3 Department of Bioengineering, Department of Materials Science & Engineering, Stanford University, Stanford, California 94305, United States.
PMID: 32894020 DOI: 10.1021/jacs.0c07276
Abstract

V-domain Ig suppressor of T-cell activation (VISTA) is an immune checkpoint that affects the ability of T-cells to attack tumors. A FRET-based high throughput screening identified NSC622608 as the first small-molecule ligand for VISTA. Investigation of the interaction of NSC622608 with VISTA using STD NMR and molecular modeling enabled the identification of a potential binding site in VISTA for NSC622608. Screening NSC622608 against a library of single-point VISTA mutants revealed the key residues in VISTA interacting with NSC622608. Further structural optimization resulted in a lead with submicromolar VISTA binding affinity. The lead compound blocked VISTA signaling in vitro, enhanced T-cell proliferation, and restored T-cell activation in the presence of VISTA-expressing Cancer cell lines. This work would enable future development of small molecules targeting VISTA as immunomodulators and imaging probes.

Figures
Products