# Development of Prostate-Specific Lysosome-Targeting Degraders

## TL;DR

This paper introduces a new method to selectively degrade proteins in prostate cancer cells using a prostate-specific receptor and lysosome-targeting degraders.

## Contribution

The novel contribution is the development of prostate-specific lysosome-targeting degraders (PTACs) that can degrade extracellular and membrane proteins in prostate cancer cells.

## Key findings

- PTACs can selectively and potently degrade extracellular and membrane proteins via the lysosome pathway in prostate cancer cells.
- Ctx-L3 and Atz-L5 achieved DC50 values of 4.3 pM for EGFR and 2 pM for PD-L1 in LNCaP cells.
- PTACs can degrade PD-L1 using both antibody- and small-molecule-based formats, showing platform versatility.

## Abstract

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.