Design, Synthesis, and Biological Evaluation of Small-Molecule PD-1/PD-L1 Inhibitors Bearing a Rigid Benz[d]oxazole...

Area of Science:

• Medicinal Chemistry
• Immunology
• Oncology

Background:

• Monoclonal antibodies targeting the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway are effective cancer immunotherapies.
• Antibody-based therapies have limitations including poor pharmacokinetics and immunogenicity.
• Small-molecule inhibitors offer a potential alternative or complementary approach to antibody therapeutics.

Purpose of the Study:

• To design and synthesize novel small-molecule inhibitors of the PD-1/PD-L1 interaction.
• To evaluate the potency and cellular activity of these inhibitors.
• To identify a lead compound for further investigation as a cancer immunotherapy agent.

Main Methods:

• Structure-activity relationship (SAR) analysis was performed on a series of biphenyl-based compounds.
• Inhibitors featured an oxadiazole motif and a benzo[d]oxazole framework.
• In vitro assays were used to determine IC50 values, cytotoxicity, and effects on T-cell function (IFN-γ secretion) and PBMC-mediated cytotoxicity.

Main Results:

• A series of biphenyl-based small molecules targeting PD-1/PD-L1 were synthesized.
• Compound I-5 demonstrated high potency with an IC50 of 8.04 nM against the PD-1/PD-L1 interaction.
• Compound I-5 showed low cytotoxicity, restored T-cell immune function by increasing IFN-γ secretion, and enhanced PBMC-mediated tumor cell killing.

Conclusions:

• Compound I-5 is a potent small-molecule inhibitor of the PD-1/PD-L1 interaction.
• I-5 exhibits favorable cellular activity, including restoration of anti-tumor immune responses.
• Compound I-5 represents a promising candidate for further development in cancer immunotherapy.