Development of Prostate-Specific Lysosome-Targeting Degraders

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Targeted protein degradation (TPD) is a promising therapeutic approach for various diseases.
• Current TPD strategies are limited in degrading membrane and extracellular proteins.

Purpose of the Study:

• To develop a novel lysosome-targeting degradation strategy for prostate cancer.
• To utilize Prostate-Specific Membrane Antigen (PSMA) as a lysosome-targeting receptor (LTR).

Main Methods:

• Developed PSMA TArgeting Chimeras (PTACs) for lysosomal degradation.
• Tested PTACs for degradation of extracellular and membrane proteins in prostate cancer cells.
• Evaluated degradation potency and selectivity of specific PTACs (Ctx-L3, Atz-L5).

Main Results:

• Demonstrated selective, potent, rapid, and sustained lysosomal degradation of target proteins.
• Achieved exceptional degradation potencies for EGFR (4.3 pM) and PD-L1 (2 pM) using Ctx-L3 and Atz-L5.
• Showcased the versatility of PTACs in antibody- and small-molecule formats for PD-L1 degradation.

Conclusions:

• The PTAC platform enables effective lysosomal degradation of extracellular and membrane proteins in prostate cancer.
• This approach advances TPD technology for precision medicine in prostate-related diseases.