Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein-tyrosine phosphatases (PTPases) form a large family of enzymes that serve as key regulatory components in signal transduction pathways. Defective or inappropriate regulation of PTPase activity leads to aberrant tyrosine phosphorylation, which contributes to the development of many human diseases including cancers and diabetes. For example, recent gene knockout studies in mice identify PTP1B as a promising target for anti-diabetes/obesity drug discovery. Thus, there is intense interest in obtaining specific and potent PTPase inhibitors for biological studies and pharmacological development. However, given the highly conserved nature of the PTPase active site, it is unclear whether selectivity in PTPase inhibition can be achieved. We describe a combinatorial approach that is designed to target both the active site and a unique peripheral site in PTP1B. Compounds that can simultaneously associate with both sites are expected to exhibit enhanced affinity and specificity. We also describe a novel affinity-based high-throughput assay procedure that can be used for PTPase inhibitor screening. The combinatorial library/high-throughput screen protocols furnished a small molecule PTP1B inhibitor that is both potent (K(i) = 2.4 nm) and selective (little or no activity against a panel of phosphatases including Yersinia PTPase, SHP1, SHP2, LAR, HePTP, PTPalpha, CD45, VHR, MKP3, Cdc25A, Stp1, and PP2C). These results demonstrate that it is possible to acquire potent, yet highly selective inhibitors for individual members of the large PTPase family of enzymes.
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PMID:Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. 1158 2

Mice lacking the protein-tyrosine phosphatase PTP1B are hypersensitive to insulin and resistant to obesity. However, the molecular basis for resistance to obesity has been unclear. Here we show that PTP1B regulates leptin signaling. In transfection studies, PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2. PTP1B is expressed in hypothalamic regions harboring leptin-responsive neurons. Compared to wild-type littermates, PTP1B(-/-) mice have decreased leptin/body fat ratios, leptin hypersensitivity, and enhanced leptin-induced hypothalamic Stat3 tyrosyl phosphorylation. Gold thioglucose treatment, which ablates leptin-responsive hypothalamic neurons, partially overcomes resistance to obesity in PTP1B(-/-) mice. Our data indicate that PTP1B regulates leptin signaling in vivo, likely by targeting Jak2. PTP1B may be a novel target to treat leptin resistance in obesity.
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PMID:PTP1B regulates leptin signal transduction in vivo. 1197 Aug 89

Protein tyrosine phosphatases (PTPs) are a large family of enzymes that catalyze the hydrolytic removal of the phosphoryl group from phosphotyrosyl (pY) proteins. PTP inhibitors provide potential treatment of human diseases/conditions such as diabetes and obesity as well as useful tools for studying the function of PTPs in signaling pathways. In this work, we have shown that certain aryl-substituted aldehydes act as reversible, slow-binding inhibitors of modest potency against PTP1B, SHP-1, and a dual-specificity phosphatase, VHR. Attachment of the tripeptide Gly-Glu-Glu to the para position of cinnamaldehyde resulted in an inhibitor (Cinn-GEE) of substantially increased potency against all three enzymes (e.g., K(I) = 5.4 microM against PTP1B). The mechanism of inhibition was investigated using Cinn-GEE specifically labeled with (13)C at the aldehyde carbon and (1)H-(13)C heteronuclear single-quantum coherence spectroscopy. While Cinn-GEE alone showed a single cross-peak at delta 9.64 ((1)H) and delta 201 ((13)C), the PTP1B/Cinn-GEE complex showed three distinct cross-peaks at delta 7.6-7.8 ((1)H) and 130-137 ((13)C). Mutation of the catalytic cysteine (Cys-215 in PTP1B) into alanine had no effect on the cross-peaks, whereas mutation of a conserved active-site arginine (Arg-221 in PTP1B) to alanine abolished all three cross-peaks. Similar experiments with Cinn-GEE that had been labeled with (13)C at the benzylic position revealed a change in the hybridization state (from sp(2) to sp(3)) for the benzylic carbon as a result of binding to PTP1B. These results rule out the possibility of a free aldehyde, aldehyde hydrate, or hemithioacetal as the enzyme-bound inhibitor form. Instead, the data are consistent with the formation of an enamine between the aldehyde group of the inhibitor and the guanidine group of Arg-221 in the PTP1B active site. These aldehydes may provide a general core structure that can be further developed into highly potent and specific PTP inhibitors.
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PMID:Peptidyl aldehydes as reversible covalent inhibitors of protein tyrosine phosphatases. 1218 56

Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents. Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity. As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors. In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity. Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes. Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4) On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family. Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds. Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.
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PMID:Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B. 1223 24

Protein tyrosine phosphatases (PTPs) control signal transduction pathways and have recently emerged as potential drug targets. Inhibition of individual PTPs can result in the activation of therapeutically relevant kinase cascades. This is particularly useful in cases where disease is associated with hormonal resistance, such as insensitivity to insulin or leptin. Currently, PTP1B is being investigated by a number of companies as a promising target for leptin/insulin mimetics and in the treatment of diabetes and obesity. Since all 90-100 PTPs have been identified in the human genome, the challenge now is to identify the function of these enzymes and the therapeutic indications that may exist for specific PTP inhibitors.
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PMID:Protein tyrosine phosphatases as drug targets: PTP1B and beyond. 1247 77

Resistance to the cellular action of insulin, a fundamental pathophysiological defect accompanying the worldwide epidemic of obesity, is closely associated with the development of type 2 diabetes mellitus and the set of cardiovascular risk factors that constitute the "metabolic" syndrome. The development of novel pharmaceutical agents that help ameliorate insulin resistance will be potentially important not only for the prevention and treatment of diabetes, but also in reducing its associated cardiovascular risk profile. Studies on the cellular role of the protein-tyrosine phosphatase PTP1B have now clearly shown that it serves as a key negative regulator of the tyrosine phosphorylation cascade integral to the insulin signaling pathway. Genetically-modified mice that lack PTP1B protein expression and animals treated with a specific PTP1B antisense oligonucleotide have provided crucial "proof-of-concept" data to show that eradicating or reducing PTP1B enhances insulin signaling and glucose tolerance. PTP1B inhibition also reduces adipose tissue storage of triglyceride under conditions of over-nutrition and was not associated with any obvious toxicity. The effects of the loss of PTP1B in vivo were also remarkably specific for components of the insulin action cascade, in spite of cellular studies suggesting that PTPIB may exert a regulatory influence on a variety of other signaling pathways. Overall, these studies have paved the way for the commercial development of PTP1B inhibitors that may serve as a novel type of "insulin sensitizer" in the management of type 2 diabetes and the cardiovascular / metabolic syndrome.
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PMID:Protein-tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2 diabetes mellitus, obesity and related states of insulin resistance. 1247 92

Protein tyrosine phosphatases (PTPs) have emerged as a new and promising class of signaling targets, since the discovery of PTP1B as a major drug target for diabetes and obesity. Blocking individual PTPs results in the activation of specific tyrosine phosphorylation events, but matching PTPs with such pathways and therapeutic indications is a complex undertaking. The history of PTP1B shows that its unusual knockout phenotype and observations with generic and antisense inhibitors in vivo, but not its classical molecular biology, triggered the rapid development of inhibitors that are today being developed for the clinic.
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PMID:Selecting protein tyrosine phosphatases as drug targets. 1254 19

Type 2 diabetes is increasing at an alarming rate worldwide, and there has been a considerable effort in several laboratories to identify suitable targets for the design of drugs against the disease. To this end, the protein tyrosine phosphatases that attenuate insulin signaling by dephosphorylating the insulin receptor (IR) have been actively pursued. This is because inhibiting the phosphatases would be expected to prolong insulin signaling and thereby facilitate glucose uptake and, presumably, result in a lowering of blood glucose. Targeting the IR protein tyrosine phosphatase, therefore, has the potential to be a significant disease-modifying strategy. Several protein tyrosine phosphatases (PTPs) have been implicated in the dephosphorylation of the IR. These phosphatases include PTPalpha, LAR, CD45, PTPepsilon, SHP2, and PTP1B. In most cases, there is evidence for and against the involvement of the phosphatases in insulin signaling. The most convincing data, however, support a critical role for PTP1B in insulin action. PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Interestingly, these mice are also resistant to diet-induced obesity when fed a high-fat diet. The insulin-sensitive phenotype of the PTP1B knockout mouse is reproduced when the phosphatase is also knocked down with an antisense oligonucleotide in obese mice. Thus PTP1B appears to be a very attractive candidate for the design of drugs for type 2 diabetes and obesity.
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PMID:Protein tyrosine phosphatases: the quest for negative regulators of insulin action. 1262 22

The identification of autophosphorylation of the insulin receptor as a pivotal component in the signal transduction induced by insulin, initiated the hunt to identify the tyrosine phosphatase(s) that were responsible for regulating dephosphorylation, and thus inactivation of the receptor. Compelling evidence for the existence of an insulin receptor specific PTP has come from the remarkable phenotype of the PTP1B deficient mouse. PTP1B deficient mice display an insulin sensitive phenotype and are able to maintain glucose homeostasis with about half the level of circulating insulin. In response to insulin administration PTP1B deficient mice have a significant increase in insulin receptor phosphorylation in liver and muscle compared to wild type controls. Unexpectedly these animals were also resistant to diet induced obesity. These observations strongly support PTP1B as a negative regulator of insulin action, thereby making it an ideal therapeutic target for intervention in type 2 diabetes and obesity.
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PMID:Protein tyrosine phosphatase 1B: a novel target for type 2 diabetes and obesity. 1267 42

Loss of Protein Tyrosine Phosphatase 1B (PTP 1B) activity is known to enhance insulin sensitivity and resistance to weight gain. So potent and orally active PTP1B inhibitors could be potential pharmacological agents for the treatment of Type 2 diabetes and obesity. Classification models of PTP1B inhibitors are developed using a data set containing 128 compounds. Their inhibitory concentrations ranged from -1.59 to 1.68 log units. Initially a two-class (active, inactive) problem is tackled using a number of different methods. The data set was divided into active and inactive classes on the basis of inhibitory activity of the compounds. Molecular structure-based descriptors were calculated and used in the model development. Descriptors encoding the flexibility of the molecules were investigated. Classification models were generated using k-nearest neighbors (k-NN), linear discriminant analysis (LDA), and radial basis function neural network (RBFNN). All models are tested using an external prediction set, compounds not used anywhere during the model development procedure. A five-descriptor model is developed that produces a classification rate of 85.7% for an external prediction set. Then a three-class (active, moderately active, inactive) problem was explored. This time the data set was divided into highly active, moderate, and inactive classes on the basis of inhibitory activity of the compounds. The best classification rate achieved for an external prediction set was 85%. The classification rates achieved indicate that these models could serve as a screening mechanism, to identify potentially useful PTP 1B inhibitors. In addition multiple linear regression and computational neural network models are also developed for prediction of log IC(50) values. All QSAR models are tested using the same external prediction set.
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PMID:Classification of inhibitors of protein tyrosine phosphatase 1B using molecular structure based descriptors. 1276 47


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