C2-Symmetrical Terphenyl Derivatives as Small Molecule Inhibitors of Programmed Cell Death 1/Programmed Death Ligand...

Area of Science:

• Immunology
• Medicinal Chemistry
• Structural Biology

Background:

• The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is a critical immune checkpoint that tumors exploit to evade immune surveillance.
• Current therapies targeting the PD-1/PD-L1 axis primarily utilize monoclonal antibodies, which present certain limitations in clinical application.
• Small molecule inhibitors represent a potential alternative to overcome the drawbacks associated with antibody-based therapies.

Purpose of the Study:

• To design, synthesize, and evaluate a novel class of small molecule compounds targeting the PD-L1 protein.
• To explore the potential of terphenyl scaffolds as a basis for developing new PD-L1 inhibitors.
• To investigate the structure-activity relationships of these compounds concerning their binding affinity to PD-L1.

Main Methods:

• Computational molecular docking was employed to design potential small molecule inhibitors.
• A series of terphenyl-based compounds were synthesized based on computational design.
• In vitro assays, including Homogeneous Time-Resolved Fluorescence (HTRF) and Nuclear Magnetic Resonance (NMR) binding assays, were used to assess compound activity and binding affinity.
• Detailed structural analysis of compound-protein interactions within the PD-L1 binding pocket was performed.

Main Results:

• A novel series of small molecule compounds based on a terphenyl scaffold were successfully designed and synthesized.
• The compounds demonstrated binding activity to PD-L1, as confirmed by HTRF and NMR assays.
• Analysis revealed correlations between the conformational arrangement of the terphenyl core's phenyl rings and the binding affinity to PD-L1.

Conclusions:

• Terphenyl-based small molecules represent a viable and promising class of inhibitors for the PD-L1 immune checkpoint.
• These compounds have the potential to overcome limitations associated with existing antibody-based therapies targeting the PD-1/PD-L1 axis.
• Further investigation into the structure-activity relationships can guide the development of more potent and effective cancer immunotherapies.