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PDBsum entry 3zm0
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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S.Grosskopf,
C.Eckert,
C.Arkona,
S.Radetzki,
K.Böhm,
U.Heinemann,
G.Wolber,
J.P.Von kries,
W.Birchmeier,
J.Rademann.
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Ref.
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Chemmedchem, 2015,
10,
815-826.
[DOI no: ]
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PubMed id
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Abstract
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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.
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