Design and synthesis of enediyne chimeras for targeted degradation of PD-L1

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Many disease-linked proteins are membrane-associated or extracellular.
• Current targeted protein degradation (TPD) methods have limitations like the hook effect and organelle dependence.
• Existing TPD strategies are not optimized for extracellular targets.

Purpose of the Study:

• To extend the Protein-Radical-Oxidation Targeting Enediyne Chimeras (PROTECs) platform for extracellular protein degradation.
• To design and evaluate a novel PROTEC molecule (Compound-1) for targeting membrane protein PD-L1.
• To assess the therapeutic potential of extracellular TPD in reversing tumor immune evasion.

Main Methods:

• Design of Compound-1, a PROTEC incorporating a PD-L1 ligand, enediyne warhead, and sulfate groups for extracellular localization.
• Evaluation of Compound-1's degradation efficacy and selectivity in HeLa cells.
• Assessment of Compound-1's impact on tumor immune evasion and cancer cell killing by peripheral blood mononuclear cells.

Main Results:

• Compound-1 potently and selectively degraded membrane PD-L1 with a DC50 of 44 nM.
• Degradation was independent of proteasomal and lysosomal pathways.
• Targeted PD-L1 degradation reversed tumor immune evasion and enhanced cancer cell killing.

Conclusions:

• The PROTEC platform can be modularly adapted for extracellular protein degradation.
• Compound-1 demonstrates the potential of extracellular TPD for cancer therapy.
• This approach offers a new strategy for targeting membrane-associated and extracellular disease proteins.