Novel Benzimidazoles as Potent Small-Molecule Inhibitors and Degraders of V-Domain Ig Suppressor of T-Cell Activation (VISTA).

The V-domain Ig suppressor of T-cell activation (VISTA) is a promising negative immune checkpoint and plays a critical role in the regulation of the quiescence of naïve T lymphocytes. Most patients however do not experience durable disease control from current immune checkpoint inhibitors and discovery of inhibitors targeting novel immune checkpoints is necessary. Herein, we report our discovery and optimization of benzimidazoles as the bifunctional inhibitors of VISTA. Compound 1 is identified as a bifunctional inhibitor targeting VISTA, which shows good binding affinity to VISTA and induces VISTA degradation in HepG2 cells through an autophagic mechanism. Compound 1 rescues VISTA-mediated immunosuppression effectively and enhances antitumor activity of immune cells. 1 activates the antitumor immunity in vivo and suppresses tumor growth in a CT26 mouse model significantly. Our results show that compound 1 is a promising VISTA inhibitor and degrader and offers novel approach for cancer immunotherapy through VISTA degradation.