A Novel Lysosome Targeting Chimera for Targeted Protein Degradation via Split-and-Mix Strategy.
ACS Chem Biol
; 19(5): 1161-1168, 2024 05 17.
Article
em En
| MEDLINE
| ID: mdl-38662199
ABSTRACT
Targeted protein degradation is becoming more and more important in the field of drug development. Compared with proteasomal-based degraders, lysosomal-based degraders have a broader target spectrum of targets, which have been demonstrated to have great potential, especially in degrading undruggable proteins. Recently, we developed a programmable and facile screening PROTAC development platform based on peptide self-assembly termed split-and-mix PROTAC (SM-PROTAC). In this study, we applied this technology for the development of lysosome-based degraders, named a split-and-mix chaperone-mediated autophagy-based degrader (SM-CMAD). We successfully demonstrated SM-CMAD as a universal platform by degrading several targets, including ERα, AR, MEK1/2, and BCR-ABL. Different from other lysosomal-based degraders, SM-CMAD was capable of facile screening with programmable ligand ratios. We believe that our work will promote the development of other multifunctional molecules and clinical translation for lysosomal-based degraders.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteólise
/
Lisossomos
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article