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Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo

Item Type:Article
Title:Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo
Creators Name:Grosskopf, S. and Eckert, C. and Arkona, C. and Radetzki, S. and Böhm, K. and Heinemann, U. and Wolber, G. and von Kries, J.P. and Birchmeier, W. and Rademann, J.
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]hydrazin o}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.
Keywords:Cancer Cell Mobility, Epithelial-Mesenchymal Transitions, Metastasis, Protein Tyrosine Phosphatases, Shp2 Inhibitors, Animals, Mice
Source:ChemMedChem
ISSN:1860-7179
Publisher:Wiley (Germany)
Volume:10
Number:5
Page Range:815-826
Date:May 2015
Official Publication:https://doi.org/10.1002/cmdc.201500015
PubMed:View item in PubMed

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