Targeted Degradation of the Oncogenic Phosphatase SHP2.
Biochemistry
; 60(34): 2593-2609, 2021 08 31.
Article
em En
| MEDLINE
| ID: mdl-34411482
ABSTRACT
SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras-MAPK pathway upon stimulation of receptor tyrosine kinases, which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at submicromolar concentrations, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazinas
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Metanol
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Proteína Tirosina Fosfatase não Receptora Tipo 11
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Neoplasias
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Antineoplásicos
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article