3ZM3

Catalytic domain of human SHP2

Summary for 3ZM3

• Entry DOI: 10.2210/pdb3zm3/pdb
• Related: 3ZM0 3ZM1 3ZM2
• Descriptor: TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 11 (2 entities in total)
• Functional Keywords: hydrolase, ptp1b
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm: Q06124
• Total number of polymer chains: 1
• Total formula weight: 33163.66

Authors

Bohm, K.,Schuetz, A.,Roske, Y.,Heinemann, U. (deposition date: 2013-02-04, release date: 2014-04-23, Last modification date: 2023-12-20)

Primary citation

Grosskopf, S.,Eckert, C.,Arkona, C.,Radetzki, S.,Bohm, K.,Heinemann, U.,Wolber, G.,Von Kries, J.,Birchmeier, W.,Rademann, J.
Selective Inhibitors of the Protein Tyrosine Phosphatase Shp2 Block Cellular Motility and Growth of Cancer Cells in Vitro and in Vivo.
Chemmedchem, 10:815-, 2015

PubMed Abstract: Selective inhibitors of the protein tyrosine phosphatase SHP2 (src homology region 2 domain phosphatase; PTPN11), an enzyme that is deregulated in numerous human tumors, were generated through a combination of chemical synthesis and structure-based rational design. Seventy pyridazolon-4-ylidenehydrazinyl benzenesulfonates were prepared and evaluated in enzyme assays. The binding modes of active inhibitors were simulated in silico using a newly generated crystal structure of SHP2. The most powerful compound, GS-493 (4-{(2Z)-2-[1,3-bis(4-nitrophenyl)-5-oxo-1,5-dihydro-4H-pyrazol-4-yliden]hydrazino}benzenesulfonic acid; 25) inhibited SHP2 with an IC50 value of 71±15 nM in the enzyme assay and was 29- and 45-fold more active toward SHP2 than against related SHP1 and PTP1B. In cell culture experiments compound 25 was found to block hepatocyte growth factor (HGF)-stimulated epithelial-mesenchymal transition of human pancreatic adenocarcinoma (HPAF) cells, as indicated by a decrease in the minimum neighbor distances of cells. Moreover, 25 inhibited cell colony formation in the non-small-cell lung cancer cell line LXFA 526L in soft agar. Finally, 25 was observed to inhibit tumor growth in a murine xenograft model. Therefore, the novel specific compound 25 strengthens the hypothesis that SHP2 is a relevant protein target for the inhibition of mobility and invasiveness of cancer cells.

PubMed: 25877780
DOI: 10.1002/CMDC.201500015

Experimental method

X-RAY DIFFRACTION (1.5 Å)