Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders.
Eur J Med Chem
; 218: 113341, 2021 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-33780898
ABSTRACT
SHP2, a non-receptor tyrosine phosphatase, plays a pivotal role in numerous oncogenic cell-signaling cascades like RAS-ERK, PI3K-AKT and JAK-STAT. On the other hand, proteolysis targeting chimera (PROTAC) has emerged as a promising strategy for the degradation of disease-related protein of interest (POI). SHP2 degradation via the PROTAC strategy will provide an alternative startegy for SHP2-mediated cancer therapy. Herein we described the design, synthesis and evaluation of a series of thalidomide-based heterobifunctional molecules and identified 11(ZB-S-29) as the highly efficient SHP2 degrader with a DC50 of 6.02 nM. Further mechanism investigation illustrated that 11 came into function through targeted SHP2 protein degradation.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Talidomida
/
Inibidores Enzimáticos
/
Proteína Tirosina Fosfatase não Receptora Tipo 11
/
Bibliotecas de Moléculas Pequenas
/
Descoberta de Drogas
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article