Selective Inhibitors of the Protein Tyrosine Phosphatase SHP2 Block Cellular Motility and Growth of Cancer Cells in vitro and in vivo. Issue 5 (15th April 2015)

• Record Type: Journal Article
• Authors: Grosskopf, Stefanie; Eckert, Chris; Arkona, Christoph; Radetzki, Silke; Böhm, Kerstin; Heinemann, Udo; Wolber, Gerhard; von Kries, Jens‐Peter; Birchmeier, Walter; Rademann, Jörg
• Is Part Of: ChemMedChem. Volume 10:Issue 5(2015:May)
• Page Start: 815
• Page End: 826
• Publication Date: 2015-04-15
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500015
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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‐{(2<italic>Z</italic>)‐2‐[1, 3‐bis(4‐nitrophenyl)‐5‐oxo‐1, 5‐dihydro‐4<italic>H</italic>‐pyrazol‐4‐yliden]hydrazino}benzenesulfonic acid; <bold>25</bold>) inhibited SHP2 with an IC<sub>50</sub> value of 71±15 n<sc>M</sc> 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 <bold>25</bold> 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, <bold>25</bold> inhibited cell colony formation in the non‐small‐cell lung cancer cell line LXFA 526L in soft agar. Finally, <bold>25</bold> was observed to inhibit tumor growth in a murine xenograft model. Therefore, the novel specific compound <bold>25</bold> strengthens the hypothesis that SHP2 is a relevant protein target for the inhibition of mobility and invasiveness of cancer cells.</p> </abstract>