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

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway blockers are successful cancer therapies.
• Limitations include low response rates and efficacy of anti-PD-1/PD-L1 monotherapy.
• V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel checkpoint regulator with potential synergistic effects.

Purpose of the Study:

• To discover novel dual small-molecule inhibitors targeting PD-1/PD-L1 and VISTA.
• To evaluate the efficacy of these inhibitors in enhancing antitumor immunity.
• To provide a new therapeutic strategy for overcoming limitations of current immunotherapies.

Main Methods:

• Discovery of benzo[d]oxazole B3 as a dual inhibitor.
• Assessment of PD-1/PD-L1 inhibitory activity and VISTA binding affinity.
• Evaluation of T-cell immunosuppression rescue, PD-L1/VISTA degradation, and in vivo antitumor efficacy in a CT26 mouse model.

Main Results:

• Benzo[d]oxazole B3 demonstrated high PD-1/PD-L1 inhibitory activity and VISTA binding affinity.
• B3 effectively rescued T-cell immunosuppression mediated by PD-L1 and VISTA, activating antitumor immunity.
• B3 induced degradation of PD-L1 and VISTA in tumor cells and showed significant in vivo antitumor efficacy.

Conclusions:

• B3 is a promising dual inhibitor of PD-1/PD-L1 and VISTA.
• B3 offers a novel therapeutic strategy to enhance antitumor immunity.
• This approach may overcome the limitations associated with current anti-PD-1/PD-L1 monotherapies.