7RCT

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

Summary for 7RCT

• Entry DOI: 10.2210/pdb7rct/pdb
• Descriptor: Tyrosine-protein phosphatase non-receptor type 11, {3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl}methanol, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: shp2 rmc-4550 phosphatase, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 121441.55

Authors

Seegar, T.C.M. (deposition date: 2021-07-08, release date: 2021-09-01, Last modification date: 2024-10-09)

Primary citation

Vemulapalli, V.,Donovan, K.A.,Seegar, T.C.M.,Rogers, J.M.,Bae, M.,Lumpkin, R.J.,Cao, R.,Henke, M.T.,Ray, S.S.,Fischer, E.S.,Cuny, G.D.,Blacklow, S.C.
Targeted Degradation of the Oncogenic Phosphatase SHP2.
Biochemistry, 60:2593-2609, 2021

PubMed 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.

PubMed: 34411482
DOI: 10.1021/acs.biochem.1c00377

Experimental method

X-RAY DIFFRACTION (1.8 Å)