New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties

Malamas, Michael S.; Sredy, Janet; Gunawan, Iwan; Mihan, Brenda; Sawicki, Diane R.; Seestaller, Laura; Sullivan, Donald; Flam, Brenda R.

doi:10.1021/jm990476x

Cited by 102 publications

(52 citation statements)

References 41 publications

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“…Changes in the intracellular enzymatic activity of PTP1B may also affect insulin action in adipose tissue from obese subjects (35). PTP1B has been recognized as a target for drug development to enhance insulin signaling through enhancing protein-tyrosine phosphorylation in the insulin action pathway (36), and novel, relatively specific inhibitors of PTP1B have been reported (37).…”

Section: Discussionmentioning

confidence: 99%

Insulin-stimulated Hydrogen Peroxide Reversibly Inhibits Protein-tyrosine Phosphatase 1B in Vivo and Enhances the Early Insulin Action Cascade

Mahadev

Zilbering

Zhu

et al. 2001

Journal of Biological Chemistry

465

348

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The insulin signaling pathway is activated by tyrosine phosphorylation of the insulin receptor and key postreceptor substrate proteins and balanced by the action of specific protein-tyrosine phosphatases (PTPases). PTPase activity, in turn, is highly regulated in vivo by oxidation/reduction reactions involving the cysteine thiol moiety required for catalysis. Here we show that insulin stimulation generates a burst of intracellular H 2 O 2 in insulin-sensitive hepatoma and adipose cells that is associated with reversible oxidative inhibition of up to 62% of overall cellular PTPase activity, as measured by a novel method using strictly anaerobic conditions. The specific activity of immunoprecipitated PTP1B, a PTPase homolog implicated in the regulation of insulin signaling, was also strongly inhibited by up to 88% following insulin stimulation. Catalase pretreatment abolished the insulin-stimulated production of H 2 O 2 as well as the inhibition of cellular PTPases, including PTP1B, and was associated with reduced insulin-stimulated tyrosine phosphorylation of its receptor and high M r insulin receptor substrate (IRS) proteins. These data provide compelling new evidence for a redox signal that enhances the early insulin-stimulated cascade of tyrosine phosphorylation by oxidative inactivation of PTP1B and possibly other tyrosine phosphatases. Protein-tyrosine phosphatases (PTPases)1 play a key role in the regulation of reversible tyrosine phosphorylation in the insulin action pathway. Insulin signaling is initiated by the phosphorylation of specific tyrosyl residues of the cell surface insulin receptor, which activates its exogenous kinase activity and promotes the phosphorylation of IRS proteins on specific tyrosine residues (1). These activation steps are balanced, in turn, by specific cellular PTPases that dephosphorylate and inactivate the receptor kinase and reverse the adapter function of the receptor substrate proteins (2). The cellular role of PTPases is apparent from the observation that highly purified insulin receptors and IRS proteins retain their tyrosine phosphorylation and activation state in vitro (3, 4), while in intact or permeabilized cells, receptor activation and substrate tyrosine phosphorylation are rapidly reversed (5-7).Since PTPases are high turnover number enzymes, physiological suppression of PTPase catalytic activity has been postulated to be a key feature of their regulation within the cellular environment to allow tyrosine phosphorylation to proceed in a balanced manner (8). PTPases have in common a conserved ϳ230-amino acid domain that contains the cysteine residue that catalyzes the hydrolysis of protein phosphotyrosine residues by the formation of a cysteinyl-phosphate intermediate (9, 10). Several laboratories have recently provided evidence that reactive oxygen species, including H 2 O 2 , can oxidize and inactivate PTPases in vivo (11,12). Since only the reduced form of the catalytic site is enzymatically active, stepwise and progressively irreversible oxidative inhibition is em...

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Section: Discussionmentioning

confidence: 99%

Insulin-stimulated Hydrogen Peroxide Reversibly Inhibits Protein-tyrosine Phosphatase 1B in Vivo and Enhances the Early Insulin Action Cascade

Mahadev

Zilbering

Zhu

et al. 2001

Journal of Biological Chemistry

465

348

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“…Covalently alkylating the site (cysteine) Azolidinediones (derivatives) (Malamas et al, 2000a) Others: Trodusquemine Phase I…”

Section: Fructose-16-bisphosphatase Inhibitorsmentioning

confidence: 99%

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Verspohl

2012

Pharmacol Rev

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“…The assay as described previously 31) and adapted for the plate reader, was used for the nanomolar detection of liberated phosphate by recombinant h-PTP 1B. 13,27,32,33) The assay used the phosphopeptide Asp-AlaAsp-Glu-phosphoTyr-Leu-Ile-Pro-Gln-Gln-Gly as substrate. This phosphorylated peptide corresponds to the 988-998 catalytic domain of epidermal growth factor receptor, and it is one of the most efficient peptide substrates known for h-PTP 1B.…”

Section: Measurement Of H-ptp 1b Inhibitionmentioning

confidence: 99%

“…88-682. 32,33,35) The color was allowed to develop at room temperature for 30 min, and the sample absorbance was determined at 630 nm using a plate reader (Bio-Tek instruments ELx 800, U.S.A.). Samples and blanks were prepared in duplicates.…”

Section: Measurement Of H-ptp 1b Inhibitionmentioning

confidence: 99%

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Bustanji

Taha

Almasri

et al. 2009

Biological & Pharmaceutical Bulletin

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Natural products have played an important role in treating and preventing human diseases.1) An analysis of the origin of the drugs that were launched in the last twenty-five years showed that both natural products and semi-synthetic compounds, derived from natural origin, comprised 34% of all new chemical entities, while 18% of them were synthetic mimics of natural compounds.2) Therefore, natural products are considered important sources for new drugs or lead optimization.2,3) The structural diversity of natural products combined with the fact that they were elaborated within living systems render them more "drug-like" than totally synthetic molecules. 4-7)Papaverine (Fig. 1A) is a prominent member of isoquinoline alkaloids isolated from opium poppy (Papaver somniferum L.).8) It exhibits non-selective smooth muscle relaxant effects, which prompted its widespread clinical use in the treatment of vasospasmic diseases.9-11) Papaverine increases the unidirectional K ϩ influx into muscles causing vasodilatation and muscle relaxant effects. The K ϩ flux is associated with increases in glucose uptake which could be one of the causes of hypoglycemia associated with papaverine use. 12)In a recent publication, we revealed a potent inhibitory action for berberine (Fig. 1B), another prominent isoquinoline alkaloid, against the anti-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B).13) The chemical similarity between berberine and papaverine combined with the fact that they share common biosynthetic origin, 14,15) prompted us to evaluate any possible inhibitory action of papaverine against h-PTP 1B. Furthermore, several reports have indicated that opiates, including papaverine, possess significant hypoglycemic properties. 16,17) The hypoglycemic mechanism of opiates is still uncertain. Furthermore, the hypoglycemic effect of papaverine is not well characterized using in vivo animal models.h-PTP 1B, a cytosolic non-receptor protein tyrosine phosphatase, has been implicated in the progression of diabetes because it acts as negative regulator of insulin signal transduction. h-PTP 1B directly catalyzes the dephosphorylation of cellular substrates of the insulin receptor kinase resulting in a down-regulation of insulin action. [18][19][20][21] Mice lacking functional h-PTP 1B showed enhanced tyrosine kinase activity and increased sensitivity to insulin. 22) In another animalbased approach, treatment with anti-sense oligonucleotide specific for h-PTP 1B resulted in normalization of blood glucose and insulin levels in animal models of type 2 diabetes. 23)Accordingly, h-PTP 1B inhibitors could increase insulin receptor tyrosine phosphorylation, mimic cellular and in vivo actions of insulin, and lower plasma glucose levels in diabetic animal models. [24][25][26][27] The current project commenced by computer-aided docking simulations to probe potential binding interactions within papaverine/h-PTP 1B complex. Subsequently, we validated our theoretical findings in vitro and in vivo. The structural similarity between papa...

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New Azolidinediones as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic Properties

Cited by 102 publications

References 41 publications

Insulin-stimulated Hydrogen Peroxide Reversibly Inhibits Protein-tyrosine Phosphatase 1B in Vivo and Enhances the Early Insulin Action Cascade

Insulin-stimulated Hydrogen Peroxide Reversibly Inhibits Protein-tyrosine Phosphatase 1B in Vivo and Enhances the Early Insulin Action Cascade

Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

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