GPC3-mediated lysosome-targeting chimeras (GLTACs) for targeted degradation of membrane proteins.
10.1016/j.apsb.2025.02.037
- Author:
Yuxin FANG
1
;
Yaojin ZHU
2
;
Wei WANG
1
;
Zhewei XIA
1
;
Shipeng HE
2
;
Guoqiang DONG
1
;
Chunquan SHENG
1
Author Information
1. Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, China.
2. Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
- Publication Type:Journal Article
- Keywords:
Glypican-3;
Lysosomal degradation;
Membrane protein;
PD-L1;
Targeted protein degradation
- From:
Acta Pharmaceutica Sinica B
2025;15(4):2156-2169
- CountryChina
- Language:English
-
Abstract:
Membrane protein degradation is a cutting-edge field in targeted protein degradation (TPD). Herein, we developed glypican-3 (GPC3)-mediated lysosome-targeting chimeras (GLTACs) as a novel strategy for the targeted degradation of tumor-specific membrane proteins. GLTACs utilize tumor-specific expression and endocytosis properties of GPC3 to degrade membrane proteins. By conjugating a GPC3-targeting peptide with the ligand of protein of interest (POI), GLTACs induce the formation of a ternary complex that is internalized into lysosomes, leading to the degradation of the POI. The effectiveness and specificity of GLTACs were validated by designing PD-L1, c-Met, and FGFR1 degraders. In particular, GLTAC WP0 potently degraded PD-L1 and induced T-cell-mediated tumor killing against HepG2 cells, highlighting the potential therapeutic applications. The development of GLTAC technology expands the scope of TPD strategies and opens new avenues for discovering novel therapeutic modalities against challenging protein targets.
