Discovery, Synthesis, and Activity Evaluation of Novel Small-Molecule Inhibitors Targeting VISTA for Cancer Immunotherapy

Immune checkpoint inhibitors (ICIs) have been potent
therapeutic
options for the treatment of multiple types of cancer. However, not
all patients experience benefits from ICIs, and discovering inhibitors
targeting novel immune checkpoints is necessary. V-domain Ig suppressor
of T-cell activation (VISTA) is a novel immune checkpoint. Blockade
of the VISTA pathway enhances antitumor immunity in multiple tumor
types. Herein, a series of VISTA inhibitors based on the benzimidazole
scaffold were discovered. B3 showed the strongest binding
affinity to the VISTA protein with a KD value of 0.452 ± 0.12 μM. In vitro, B3 could effectively activate VISTA-mediated immunosuppression
and induce effective VISTA degradation in HepG2 cells. In
vivo, B3 improved pharmacokinetics compared
to the lead compound 4. Moreover, compound B3 significantly inhibited tumor growth in a CT26 colon cancer model.
These results suggest that compound B3 is a promising
VISTA small molecule inhibitor and degrader worthy of further development
as an antitumor agent.