7rct

Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor RMC-4550

spinqualitylabelsall models 7rct, resolution 1.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.8Å Ligands: 4Q4, CL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Targeted Degradation of the Oncogenic Phosphatase SHP2.,Vemulapalli V, Donovan KA, Seegar TCM, Rogers JM, Bae M, Lumpkin RJ, Cao R, Henke MT, Ray SS, Fischer ES, Cuny GD, Blacklow SC Biochemistry. 2021 Aug 31;60(34):2593-2609. doi: 10.1021/acs.biochem.1c00377., Epub 2021 Aug 19. PMID:34411482 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine phosphatase 3D structures

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