Development of Prostate-Specific Lysosome-Targeting Degraders.

Targeted protein degradation (TPD) technologies have emerged as transformative therapeutic modality for treating cancers and other diseases. While significant progress has been achieved in intracellular protein degradation, degradation of membrane proteins and extracellular targets remains in an early stage. In this study, we developed a prostate-specific lysosome-targeting degradation strategy using a prostate-specific membrane antigen (PSMA) as a lysosome-targeting receptor (LTR). We demonstrated that both extracellular and membrane proteins can be selectively degraded in prostate cancer cells via the lysosome pathway. These PSMA TArgeting Chimeras (PTACs) were shown to facilitate lysosomal degradation in a selective, potent, rapid, and sustained manner. Notably, Ctx-L3 and Atz-L5 exhibited exceptional degradation potencies in LNCaP cells, with DC50 values of 4.3 pM for EGFR and 2 pM for PD-L1, respectively─among the most potent degraders reported to date. Furthermore, the application of PTACs to degrade PD-L1, using both antibody- and small-molecule-based formats, highlights the versatility of this platform. Collectively, this work advances the application of TPD technology and offers promising avenues for precision medicine in prostate-related diseases.