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.