The Experts below are selected from a list of 36729 Experts worldwide ranked by ideXlab platform
Kazuo Koike - One of the best experts on this subject based on the ideXlab platform.
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Identification of flavonolignans from Silybum marianum seeds as allosteric Protein Tyrosine Phosphatase 1B inhibitors.
Journal of enzyme inhibition and medicinal chemistry, 2018Co-Authors: Ningbo Qin, Tatsunori Sasaki, Jian Wang, Xiangyu Zhang, Maosheng Cheng, Hui-ming Hua, Kazuo KoikeAbstract:Protein Tyrosine Phosphatase 1B (PTP1B) is an attractive molecular target for anti-diabetes, anti-obesity, and anti-cancer drug development. From the seeds of Silybum marianum, nine flavonolignans,...
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Protein Tyrosine Phosphatase 1b inhibitory activity of lavandulyl flavonoids from roots of sophora flavescens
Planta Medica, 2014Co-Authors: Tatsunori Sasaki, Koji Higai, Tran Hong Quang, Young Ho Kim, Kazuo KoikeAbstract:Protein Tyrosine Phosphatase 1B is a non-transmembrane Protein Tyrosine Phosphatase and major negative regulator in insulin signaling cascades, and much attention has been paid to Protein Tyrosine Phosphatase 1B inhibitors as potential therapies for diabetes. The screening of a natural compound library led to the discovery of five lavandulyl flavonoids, which were isolated from the roots of Sophora flavescens, as novel PTP1B inhibitors: kuraridin (1), norkurarinone (2), kurarinone (3), 2′-methoxykurarinone (4), and kushenol T (5). The three most potent compounds, 1, 2, and 4 (IC50 < 30 µM), were demonstrated to be noncompetitive inhibitors of Protein Tyrosine Phosphatase 1B based on a kinetic analysis, and they exhibited different inhibitory selectivities against four homologous Protein Tyrosine Phosphatases (T cell Protein Tyrosine Phosphatase, vaccinia H1-related Phosphatase, and Src homology domain 2-containing Protein Tyrosine Phosphatases 1 and 2). Compounds 1, 2, and 4 also exhibited cellular activity in the insulin signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, suggesting their potential for new anti-insulin-resistant drug developments.
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Protein Tyrosine Phosphatase 1B inhibitory activity of lavandulyl flavonoids from roots of Sophora flavescens.
Planta medica, 2014Co-Authors: Tatsunori Sasaki, Koji Higai, Tran Hong Quang, Young Ho Kim, Kazuo KoikeAbstract:Protein Tyrosine Phosphatase 1B is a non-transmembrane Protein Tyrosine Phosphatase and major negative regulator in insulin signaling cascades, and much attention has been paid to Protein Tyrosine Phosphatase 1B inhibitors as potential therapies for diabetes. The screening of a natural compound library led to the discovery of five lavandulyl flavonoids, which were isolated from the roots of Sophora flavescens, as novel PTP1B inhibitors: kuraridin (1), norkurarinone (2), kurarinone (3), 2′-methoxykurarinone (4), and kushenol T (5). The three most potent compounds, 1, 2, and 4 (IC50
Tatsunori Sasaki - One of the best experts on this subject based on the ideXlab platform.
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Identification of flavonolignans from Silybum marianum seeds as allosteric Protein Tyrosine Phosphatase 1B inhibitors.
Journal of enzyme inhibition and medicinal chemistry, 2018Co-Authors: Ningbo Qin, Tatsunori Sasaki, Jian Wang, Xiangyu Zhang, Maosheng Cheng, Hui-ming Hua, Kazuo KoikeAbstract:Protein Tyrosine Phosphatase 1B (PTP1B) is an attractive molecular target for anti-diabetes, anti-obesity, and anti-cancer drug development. From the seeds of Silybum marianum, nine flavonolignans,...
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Protein Tyrosine Phosphatase 1b inhibitory activity of lavandulyl flavonoids from roots of sophora flavescens
Planta Medica, 2014Co-Authors: Tatsunori Sasaki, Koji Higai, Tran Hong Quang, Young Ho Kim, Kazuo KoikeAbstract:Protein Tyrosine Phosphatase 1B is a non-transmembrane Protein Tyrosine Phosphatase and major negative regulator in insulin signaling cascades, and much attention has been paid to Protein Tyrosine Phosphatase 1B inhibitors as potential therapies for diabetes. The screening of a natural compound library led to the discovery of five lavandulyl flavonoids, which were isolated from the roots of Sophora flavescens, as novel PTP1B inhibitors: kuraridin (1), norkurarinone (2), kurarinone (3), 2′-methoxykurarinone (4), and kushenol T (5). The three most potent compounds, 1, 2, and 4 (IC50 < 30 µM), were demonstrated to be noncompetitive inhibitors of Protein Tyrosine Phosphatase 1B based on a kinetic analysis, and they exhibited different inhibitory selectivities against four homologous Protein Tyrosine Phosphatases (T cell Protein Tyrosine Phosphatase, vaccinia H1-related Phosphatase, and Src homology domain 2-containing Protein Tyrosine Phosphatases 1 and 2). Compounds 1, 2, and 4 also exhibited cellular activity in the insulin signaling pathway by increasing the insulin-stimulated Akt phosphorylation level in human hepatocellular liver carcinoma HepG2 cells, suggesting their potential for new anti-insulin-resistant drug developments.
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Protein Tyrosine Phosphatase 1B inhibitory activity of lavandulyl flavonoids from roots of Sophora flavescens.
Planta medica, 2014Co-Authors: Tatsunori Sasaki, Koji Higai, Tran Hong Quang, Young Ho Kim, Kazuo KoikeAbstract:Protein Tyrosine Phosphatase 1B is a non-transmembrane Protein Tyrosine Phosphatase and major negative regulator in insulin signaling cascades, and much attention has been paid to Protein Tyrosine Phosphatase 1B inhibitors as potential therapies for diabetes. The screening of a natural compound library led to the discovery of five lavandulyl flavonoids, which were isolated from the roots of Sophora flavescens, as novel PTP1B inhibitors: kuraridin (1), norkurarinone (2), kurarinone (3), 2′-methoxykurarinone (4), and kushenol T (5). The three most potent compounds, 1, 2, and 4 (IC50
Benjamin G Neel - One of the best experts on this subject based on the ideXlab platform.
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revealing mechanisms for sh2 domain mediated regulation of the Protein Tyrosine Phosphatase shp 2
Structure, 1998Co-Authors: David Barford, Benjamin G NeelAbstract:The crystal structure of the Protein Tyrosine Phosphatase SHP-2 reveals the mechanism of auto-inhibition of Phosphatase activity by its SH2 domains. PhosphoTyrosine peptide stimulation of the Phosphatase activity, resulting from peptide binding to the N-terminal SH2 domain, is linked to conformational changes within the Protein, including an unprecedented allosteric transition of the N-terminal SH2 domain.
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expression purification and characterization of sh2 containing Protein Tyrosine Phosphatase sh ptp2
Journal of Biological Chemistry, 1993Co-Authors: S Sugimoto, R J Lechleider, Steven E Shoelson, Benjamin G Neel, Christopher T WalshAbstract:A human Protein Tyrosine Phosphatase containing two src homology 2 (SH2) domains (SH-PTP2) was expressed in Escherichia coli under T7 promoter control and purified to near homogeneity. The purified Protein, with molecular mass of 68 kDa on SDS-polyacrylamide gel electrophoresis, was identified as SH-PTP2 by its Protein Tyrosine Phosphatase activity and N-terminal amino acid sequence analysis. Its Protein Tyrosine Phosphatase activity was sensitive to pH and salt concentration. Whereas its optimum pH for the low molecular weight substrate para-nitrophenyl phosphate is 5.6, the pH optima for peptide substrates were shifted toward neutral. With the artificial Protein substrate reduced, carboxyamidomethylated, and maleylated lysozyme, it displays 2000-fold lower Km (1.7 microM) and 2.4-fold higher kcat (0.11 s-1) than with para-nitrophenyl phosphate. Among the phosphopeptides from autophosphorylation sites of receptors for epidermal growth factor and platelet-derived growth factor, SH-PTP2 displayed high activity toward phosphopeptides corresponding to pY992 of the epidermal growth factor receptor and pY1009 and pY1021 of the platelet-derived growth factor receptor. In further enzymatic studies with phosphopeptides corresponding to pY1009, SH-PTP2 showed nonlinear Line-weaver-Burk double-reciprocal plots, suggesting that the phosphopeptide corresponding to pY1009 may have a substrate and allosteric effect.
Dayong Shi - One of the best experts on this subject based on the ideXlab platform.
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Inhibitor binding sites in the Protein Tyrosine Phosphatase SHP-2.
Mini reviews in medicinal chemistry, 2020Co-Authors: Haonan Zhang, Zhengquan Gao, Chunxiao Meng, Dayong ShiAbstract:Protein Tyrosine Phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over Protein Tyrosine Phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.
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design synthesis and biological evaluation of bromophenol derivatives as Protein Tyrosine Phosphatase 1b inhibitors
ChemInform, 2012Co-Authors: Bo Jiang, Dayong Shi, Yongchao Cui, Shuju GuoAbstract:A variety of bromophenol derivatives with bicyclic, tricyclic or tetracyclic scaffold is synthesized and evaluated for Protein Tyrosine Phosphatase 1B inhibitory activity.
Michael R. Jirousek - One of the best experts on this subject based on the ideXlab platform.
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Protein Tyrosine Phosphatase 1B inhibitors for diabetes
Nature Reviews Drug Discovery, 2002Co-Authors: Theodore O. Johnson, Jacques Ermolieff, Michael R. JirousekAbstract:Obesity and type 2 diabetes have become epidemic medical problems and will cause significant morbidity and mortality if new therapeutic agents cannot be brought forward. Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be involved in the negative regulation of both insulin and leptin action at the in vitro, ex vivo and in vivo levels. A growing body of human genetic data also support the hypothesis that PTP1B has an important role in insulin signalling and possibly in obesity in humans. PTP1B has been implicated in diabetes and obesity in knockout-mouse studies on a normal background. When crossed onto ob/ob mice, improvement in blood glucose and obesity is seen. When Ptp1b antisense oligonucleotides are administered in vivo to ob/ob mice, normalized blood glucose levels are obtained. Insulin sensitivity is improved at the cellular level. PTP1B is tractable to structure-based drug design, and the crystal structure is well known. Recently, the crystal structure of the closely related T-cell Protein Tyrosine Phosphatase (TCPTP) has become available, raising the possibility for designing selective inhibitors. Potent ( K _i values in the nM range) inhibitors of PTP1B are known, and oxamic acids are a common structural motif found in these compounds. The high polar surface area (PSA) and charge of this functionality make further optimization difficult, and an intense search to uncover phosphoTyrosine mimetics with improved physico-chemical properties is in progress. Pro-drugs of the oxamic acids and replacement of the acid functionality with isosteric functional groups might provide compounds with improved physico-chemical properties. Lipophilic compounds have been reported — one of the two reported structures seems to be a competitive inhibitor of PTP1B and the other does not. This highlights the need for a clear understanding of the mechanism of inhibition and an understanding of the kinetics of compounds. Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein Tyrosine Phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this Phosphatase.
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Protein Tyrosine Phosphatase 1b inhibitors for diabetes
Nature Reviews Drug Discovery, 2002Co-Authors: Theodore O. Johnson, Jacques Ermolieff, Michael R. JirousekAbstract:Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein Tyrosine Phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this Phosphatase.
