PSMA-Targeting Chimeras for Cell-Type-Specific Degradation of Surface Immune Checkpoint Protein PD-L1

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Lysosome-targeting chimeras degrade proteins via the endosome-lysosome pathway.
• Current methods are limited by receptor expression for endocytosis.
• Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, enabling targeted therapies.

Purpose of the Study:

• To develop a novel class of small molecules, PSMA-targeting chimeras (PATACs), for membrane protein degradation.
• To leverage PSMA's specific expression in prostate cancer for targeted therapy.
• To demonstrate the efficacy of PATACs in degrading target proteins and enhancing anti-cancer immunity.

Main Methods:

• Development of heterobispecific small molecules (PATACs) targeting PSMA.
• Utilizing PATACs to co-internalize target proteins into the lysosome for degradation.
• Assessing the degradation of programmed cell death ligand 1 (PD-L1) by a representative PATAC (A4).
• Evaluating the impact of PD-L1 degradation on T-cell-mediated killing in a coculture system.
• Employing molecular dynamics simulations to analyze complex stability.

Main Results:

• A representative PATAC, A4, induced rapid and dose-dependent degradation of PD-L1 within 4 hours at 100 nM.
• Degradation of PD-L1 by A4 significantly enhanced T-cell-mediated killing of LNCaP cells.
• Molecular dynamics simulations showed enhanced conformational stability of the PSMA-A4-PD-L1 ternary complex due to a rigid linker.

Conclusions:

• PATACs represent a novel and accessible class of bifunctional small molecules for membrane protein degradation.
• This technology enables precise manipulation of membrane proteins via the PSMA receptor.
• PATACs hold promise as a new modality for targeted therapy in prostate cancer.