title: Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo.
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.
authors: Institut für Pharmazie/Institut für Chemie, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin (Germany) http://www.bcp.fu-berlin.de/ag-rademann; Leibniz-Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Str. 10, 13125 Berlin (Germany); Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Str. 10, 13125 Berlin (Germany).
authors: Stefanie
authors: S
authors: Grosskopf
authors: Chris
authors: C
authors: Eckert
authors: Christoph
authors: C
authors: Arkona
authors: Silke
authors: S
authors: Radetzki
authors: Kerstin
authors: K
authors: Böhm
authors: Udo
authors: U
authors: Heinemann
authors: Gerhard
authors: G
authors: Wolber
authors: Jens-Peter
authors: JP
authors: von Kries
authors: Walter
authors: W
authors: Birchmeier
authors: Jörg
authors: J
authors: Rademann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: SHP2 inhibitors; cancer cell mobility; epithelial-mesenchymal transitions; metastasis; protein tyrosine phosphatases