Discovery of Novel Small-Molecule Inhibitors of PD-1/PD-L1 Interaction via Structural Simplification Strategy

Area of Science:

• Immunology
• Pharmacology
• Medicinal Chemistry

Background:

• The programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway is a key target in cancer immunotherapy.
• Monoclonal antibodies (mAbs) targeting PD-1/PD-L1 have shown efficacy but face limitations like poor penetration and high cost.
• Small-molecule inhibitors offer potential advantages over mAbs, but their development is challenging.

Purpose of the Study:

• To discover novel, drug-like small-molecule inhibitors of the PD-1/PD-L1 interaction.
• To identify potent inhibitors with improved properties compared to existing therapies.

Main Methods:

• Structure-based drug design and medicinal chemistry optimization.
• Synthesis and in vitro evaluation of small-molecule inhibitors.
• Biochemical assays to determine inhibitory activity (IC50) and binding affinity (KD).
• Cell-based assays to assess functional immune response (IFN-γ production).

Main Results:

• A series of novel PD-1/PD-L1 inhibitors were synthesized, starting from BMS-1058.
• Compound A9 demonstrated potent PD-L1 inhibition (IC50 = 0.93 nM) and high binding affinity (KD = 3.64 nM).
• A9 significantly promoted Interferon-gamma (IFN-γ) production by restoring T-cell activity in co-culture assays.

Conclusions:

• Compound A9 is a highly promising small-molecule inhibitor of the PD-1/PD-L1 interaction.
• A9 exhibits potent anti-cancer immune activity and warrants further investigation for therapeutic development.