PMID- 18480264
OWN - NLM
STAT- MEDLINE
DCOM- 20080624
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 105
IP  - 20
DP  - 2008 May 20
TI  - Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by 
      high-throughput docking.
PG  - 7275-80
LID - 10.1073/pnas.0710468105 [doi]
AB  - The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor 
      signaling. Gain-of-function mutations in several types of leukemia define Shp2 as 
      a bona fide oncogene. We performed a high-throughput in silico screen for 
      small-molecular-weight compounds that bind the catalytic site of Shp2. We have 
      identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and 
      cell-permeable inhibitor, which is specific for Shp2 over the closely related 
      tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular 
      events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced 
      epithelial cell scattering and branching morphogenesis. PHPS1 also blocks 
      Shp2-dependent downstream signaling, namely HGF/SF-induced sustained 
      phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. 
      Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the 
      leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent 
      growth of a variety of human tumor cell lines. The PHPS compound class is 
      therefore suitable for further development of therapeutics for the treatment of 
      Shp2-dependent diseases.
FAU - Hellmuth, Klaus
AU  - Hellmuth K
AD  - Max Delbruck Center for Molecular Medicine, Robert Rossle Strasse 10, D-13125 
      Berlin, Germany.
FAU - Grosskopf, Stefanie
AU  - Grosskopf S
FAU - Lum, Ching Tung
AU  - Lum CT
FAU - Wurtele, Martin
AU  - Wurtele M
FAU - Roder, Nadine
AU  - Roder N
FAU - von Kries, Jens Peter
AU  - von Kries JP
FAU - Rosario, Marta
AU  - Rosario M
FAU - Rademann, Jorg
AU  - Rademann J
FAU - Birchmeier, Walter
AU  - Birchmeier W
LA  - eng
PT  - Journal Article
DEP - 20080514
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Benzenesulfonates)
RN  - 0 (Hydrazones)
RN  - 0 (Pyrazolones)
RN  - 0 (phenylhydrazonopyrazolone sulfonate 1)
RN  - 39455-90-8 (pyrazolone)
RN  - 67256-21-7 (Hepatocyte Growth Factor)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Animals
MH  - Benzenesulfonates/chemistry/*pharmacology
MH  - Catalytic Domain
MH  - Dogs
MH  - *Drug Screening Assays, Antitumor
MH  - *Gene Expression Regulation
MH  - Hepatocyte Growth Factor/metabolism
MH  - Humans
MH  - Hydrazones/chemistry/*pharmacology
MH  - Kinetics
MH  - Leukemia/metabolism
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Models, Biological
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism/*physiology
MH  - Pyrazolones/chemistry
MH  - Structure-Activity Relationship
PMC - PMC2438240
COIS- The authors declare no conflict of interest.
EDAT- 2008/05/16 09:00
MHDA- 2008/06/25 09:00
PMCR- 2008/11/20
CRDT- 2008/05/16 09:00
PHST- 2008/05/16 09:00 [pubmed]
PHST- 2008/06/25 09:00 [medline]
PHST- 2008/05/16 09:00 [entrez]
PHST- 2008/11/20 00:00 [pmc-release]
AID - 0710468105 [pii]
AID - 0033 [pii]
AID - 10.1073/pnas.0710468105 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2008 May 20;105(20):7275-80. doi: 
      10.1073/pnas.0710468105. Epub 2008 May 14.