Discovery of Benzo[<i>d</i>]oxazoles as Novel Dual Small-Molecule Inhibitors Targeting PD-1/PD-L1 and VISTA Pathway

The blockers of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway have achieved great clinical success. However, the limited efficacy and low tumor response rate of anti-PD-1/PD-L1 monotherapy limit the clinical application of PD-1/PD-L1 inhibitors. V-domain immunoglobulin suppressor of T-cell activation (VISTA), a novel checkpoint regulator, exhibits potential synergy with PD-1/PD-L1 in enhancing antitumor immunity. Herein, we report the discovery of benzo[<i>d</i>]oxazole <b>B3</b> as novel dual small-molecule inhibitors targeting PD-1/PD-L1 and VISTA with high PD-1/PD-L1 inhibitory activity and VISTA binding affinity. <b>B3</b> rescues the immunosuppression of T-cells mediated by PD-L1 and VISTA and activates antitumor immunity effectively. Moreover, <b>B3</b> could induce degradation of PD-L1 and VISTA in tumor cell. Furthermore, <b>B3</b> displays significant <i>in vivo</i> antitumor efficacy in a CT26 mouse model. Our results discover <b>B3</b> as a promising dual PD-1/PD-L1 and VISTA inhibitor, providing a novel therapeutic strategy to overcome the limitations of current anti-PD-1/PD-L1 therapy.