title: Discovery of a Novel Inhibitor of the Protein Tyrosine Phosphatase Shp2.
abstract: Shp2 is a ubiquitously expressed protein tyrosine phosphatase (PTP) related to adult acute myelogenous leukemia and human solid tumors. In this report, we describe identification of a potent Shp2 inhibitor, Fumosorinone (Fumos) from entomogenous fungi, which shows selective inhibition of Shp2 over other tested PTPs. Using a surface plasmon resonance analysis, we further confirmed the physical interaction between Shp2 and Fumos. Fumos inhibits Shp2-dependent activation of the Ras/ERK signal pathway downstream of EGFR, and interrupts EGF-induced Gab1-Shp2 association. As expected, Fumos shows little effects on the Shp2-independent ERK1/2 activation induced by PMA or oncogenic Ras. Furthermore, Fumos down-regulates Src activation, inhibits phosphorylation of Paxillin and prevents tumor cell invasion. These results suggest that Fumos can inhibit Shp2-dependent cell signaling in human cells and has a potential for treatment of Shp2-associated diseases.
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Cao
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Cuicui
authors.initials: C
authors.lastname: Wang
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Fan
authors.initials: F
authors.lastname: Liang
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Yan
authors.affiliation: College of Life Science, Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, Hebei University, Baoding, Hebei 071002, P.R. China.
authors.forename: Duqiang
authors.initials: D
authors.lastname: Luo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D051419:Paxillin / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C496061:PXN protein, human; D051419:Paxillin; D011728:Pyridones; C000599091:fumosorinone; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D015689:Oncogene Protein p21(ras)