Novel Biphenyl Pyridines as Potent Small-Molecule Inhibitors Targeting the Programmed Cell Death-1/Programmed Cell...

Area of Science:

• Oncology
• Immunology
• Medicinal Chemistry

Background:

• Targeting the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis with monoclonal antibodies is a successful cancer therapy strategy.
• Limitations of antibodies necessitate the development of small-molecule inhibitors for the PD-1/PD-L1 pathway.

Purpose of the Study:

• To design, synthesize, and evaluate novel biphenyl pyridine derivatives as small-molecule inhibitors of the PD-1/PD-L1 interaction.
• To identify a potent and orally bioavailable small-molecule inhibitor for cancer immunotherapy.

Main Methods:

• Synthesis of novel biphenyl pyridine compounds.
• In vitro evaluation of PD-1/PD-L1 interaction inhibition (IC50 determination).
• In vivo assessment of antitumor activity, pharmacokinetics, and immune cell activation in a CT26 mouse model.

Main Results:

• Compound 24 potently inhibited the PD-1/PD-L1 interaction with an IC50 of 3.8 ± 0.3 nM.
• Compound 24 exhibited 22% oral bioavailability and significant in vivo antitumor efficacy.
• Flow cytometry and immunohistochemistry confirmed compound 24's activation of anti-tumor immune responses.

Conclusions:

• Compound 24 is a promising small-molecule inhibitor of the PD-1/PD-L1 axis.
• The developed compound warrants further investigation for cancer immunotherapy applications.