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.