Discovery of Novel PD-L1 Inhibitors That Induce the Dimerization, Internalization, and Degradation of PD-L1 Based on...

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Tumor cells evade immune surveillance by overexpressing programmed cell death-ligand 1 (PD-L1), which interacts with programmed cell death-1 (PD-1).
• Tumor-intrinsic PD-L1 contributes to tumor progression independently of PD-1 interaction, posing challenges for inhibitor development.

Purpose of the Study:

• To discover novel PD-L1 inhibitors using a fragment coupling strategy.
• To investigate the mechanism of action and therapeutic potential of newly identified inhibitors.

Main Methods:

• Fragment coupling strategy for inhibitor discovery.
• Biochemical assays to determine IC50 values for PD-1/PD-L1 interaction inhibition.
• In vitro studies on PD-L1 dimerization, internalization, and degradation.
• In vivo efficacy studies in the CT26 mouse model.

Main Results:

• Compound B9 identified as a potent inhibitor of PD-1/PD-L1 interaction with an IC50 of 1.8 ± 0.7 nM.
• B9 promotes PD-L1 dimerization, internalization, and degradation, extending beyond simple axis blockade.
• Significant in vivo antitumor efficacy observed in the CT26 mouse model.
• B9 activated the tumor immune microenvironment and induced PD-L1 degradation within the tumor.

Conclusions:

• B9 represents a promising lead compound for PD-L1 targeted therapy.
• The dual mechanism of blocking PD-1/PD-L1 interaction and functionally inhibiting PD-L1 signaling offers a novel therapeutic approach.
• B9's ability to induce PD-L1 degradation warrants further investigation for cancer treatment.