蛋白磷酸酶2
细胞生物学
双特异性磷酸酶
磷酸化
PTPN11型
脱磷
生物化学
生物
原癌基因酪氨酸蛋白激酶Src
激酶
蛋白磷酸酶1
信号转导
作者
Vidyasiri Vemulapalli,Katherine A. Donovan,Tom C. M. Seegar,Julia M. Rogers,Munhyung Bae,Ryan J. Lumpkin,Ruili Cao,Matthew T. Henke,Soumya S. Ray,Eric S. Fischer,Gregory D. Cuny,Stephen C. Blacklow
出处
期刊:Biochemistry
[American Chemical Society]
日期:2021-06-02
卷期号:60 (34): 2593-2609
被引量:2
标识
DOI:10.1021/acs.biochem.1c00377
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI