Protein tyrosine phosphatase-based therapeutics: lessons from PTP1B

Andersen, Jannik N.; Tonks, Nicholas K.

doi:10.1007/978-3-540-40035-6_11

Cited by 13 publications

(12 citation statements)

References 84 publications

(125 reference statements)

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“…With the validation of PTP1B as a therapeutic target for the treatment of diabetes and obesity, interest has grown in exploiting the PTPs for development of small‐molecule drugs . Nevertheless, the reactivity of the essential active‐site cysteine has posed a significant challenge to the generation of reversible active‐site‐directed inhibitors . In the many high throughput screens of small‐molecule libraries that have been conducted to date in industry and academia, it has become apparent that the presence of this potent nucleophile at the catalytic center renders the PTPs sensitive to the effects of Michael acceptors, leading to irreversible inhibition of PTP function.…”

Section: Discussionmentioning

confidence: 99%

The anti‐inflammatory compound BAY‐11‐7082 is a potent inhibitor of protein tyrosine phosphatases

Krishnan

Bencze

Cohen³

et al. 2013

The FEBS Journal

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Summary The families of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) function in a coordinated manner to regulate signal transduction events that are critical for cellular homeostasis. Aberrant tyrosine phosphorylation, resulting from disruption of either PTP or PTK function, has been shown to be the cause of major human diseases, including cancer and diabetes. Consequently, the characterization of small molecule inhibitors of these kinases and phosphatases may not only provide molecular probes with which to define the significance of particular signalling events, but also may have therapeutic implications. BAY 11-7082 is an anti-inflammatory compound that has been reported to inhibit IκB kinase activity. The compound has an α,β-unsaturated electrophilic center, which confers the property of being a Michael acceptor; this suggests that it may react with nucleophilic cysteine-containing proteins, such as PTPs. In this study, we demonstrated that BAY 11-7082 was a potent, irreversible inhibitor of PTPs. Using mass spectrometry, we have shown that BAY 11-7082 inactivated PTPs by forming a covalent adduct with the active site cysteine. Administration of the compound caused an increase in protein tyrosine phosphorylation in RAW 264 macrophages, similar to the effects of the generic PTP inhibitor sodium orthovanadate. These data illustrate that BAY 11-7082 is an effective pan-PTP inhibitor with cell permeability, revealing its potential as a new probe for chemical biology approaches to the study of PTP function. Furthermore, the data suggest that inhibition of PTP function may contribute to the many biological effects of BAY 11-7082 that have been reported to date.

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Section: Discussionmentioning

confidence: 99%

The anti‐inflammatory compound BAY‐11‐7082 is a potent inhibitor of protein tyrosine phosphatases

Krishnan

Bencze

Cohen³

et al. 2013

The FEBS Journal

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“…Most prominent among these is PTP1B, which has been implicated in the downregulation of insulin signaling by a variety of approaches, including the phenotype of the PTP1B knock-out mouse (44,45). This and the identification of this phosphatase as a regulator of signaling in response to cytokines such as leptin (46 -48) have led to considerable attention being focused on PTP1B as a target for development of novel therapeutics for treatment of both diabetes and obesity (49,50). In our analysis, we observed that insulin stimulation induced the rapid and transient oxidation and inactivation of PTP1B.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Insulin Signaling through Reversible Oxidation of the Protein-tyrosine Phosphatases TC45 and PTP1B

Meng

Buckley

Galić

et al. 2004

Journal of Biological Chemistry

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Many studies have illustrated that the production of reactive oxygen species (ROS) is important for optimal tyrosine phosphorylation and signaling in response to diverse stimuli. Protein-tyrosine phosphatases (PTPs), which are important regulators of signal transduction, are exquisitely sensitive to inhibition after generation of ROS, and reversible oxidation is becoming recognized as a general physiological mechanism for regulation of PTP function. Thus, production of ROS facilitates a tyrosine phosphorylation-dependent cellular signaling response by transiently inactivating those PTPs that normally suppress the signal. In this study, we have explored the importance of reversible PTP oxidation in the signaling response to insulin. Using a modified ingel PTP assay, we show that stimulation of cells with insulin resulted in the rapid and transient oxidation and inhibition of two distinct PTPs, which we have identified as PTP1B and TC45, the 45-kDa spliced variant of the T cell protein-tyrosine phosphatase. We investigated further the role of TC45 as a regulator of insulin signaling by combining RNA interference and the use of substrate-trapping mutants. We have shown that TC45 is an inhibitor of insulin signaling, recognizing the ␤-subunit of the insulin receptor as a substrate. The data also suggest that this strategy, using ligand-induced oxidation to tag specific PTPs and using interference RNA and substrate-trapping mutants to illustrate their role as regulators of particular signal transduction pathways, may be applied broadly across the PTP family to explore function.The reversible phosphorylation of tyrosyl residues in proteins, catalyzed by the coordinated actions of protein tyrosine kinases and protein-tyrosine phosphatases (PTPs), 1 is of paramount importance to the control of such fundamental physiological functions as cell proliferation, differentiation, survival, metabolism, and motility (1, 2). The phosphorylation of a target protein alters its function, including changes in enzymatic activity or its ability to associate with other proteins. In response to a stimulus, such as a growth factor or hormone, multiple phosphorylation and dephosphorylation reactions are coordinated in signal transduction cascades that culminate in the physiological response (3, 4). A characterization of the enzymes responsible for the regulation of protein tyrosine phosphorylation in vivo will be essential for an understanding of the control of signal transduction under normal and pathophysiological conditions and would be expected to identify important new targets for therapeutic intervention in human disease. We are focusing on this process from the perspective of the PTP family of enzymes.A substantial body of information has been accumulated to describe the role of protein tyrosine kinases in the regulation of signal transduction. In contrast, we are only now beginning to appreciate in mechanistic detail the role of some members of the PTP family in fine-tuning the signaling response to extracellular stimuli. Analysis ...

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“…These endeavors have been strongly supported by the availability of an impressive number of x-ray structures (reviewed in Ref. 56). Furthermore, the seminal publications that demonstrated that PTP1B is a key negative regulator of insulin and leptin signaling (6 -9) provided the first evidence that PTPs indeed could be attractive molecular targets.…”

Section: Discussionmentioning

confidence: 99%

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

Lund

Andersen

Iversen

et al. 2004

Journal of Biological Chemistry

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Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTP␤ over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTP␤, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs.Protein-tyrosine phosphatases (PTPs) 1 are key regulators of signal transduction. Together with the counteracting proteintyrosine kinases, they control the phosphorylation status of many important proteins and are thereby critically involved in the regulation of fundamental cellular processes such as metabolism, cell growth, and differentiation. Aberrant tyrosine phosphorylation levels have been associated with the development of cancer, autoimmunity, and diabetes, thus indicating that PTPs might play important etiological and pathogenic roles in these diseases (1-5). In particular, two elegant studies with PTP1B knockout mice, in which increased insulin sensitivity and resistance to diet-induced obesity were observed (6, 7), indicated that PTP1B is an important negative regulator of insulin and leptin action, suggesting that inhibition of this enzyme could augment and prolong insulin and leptin signaling (8, 9). As a result, a number of academic and industrial laboratories have devoted considerable efforts toward the development of selective inhibitors of PTP1B for treatment of type 2 diabetes and obesity resulting in very significant progress (reviewed in Refs. 10 -12). The field has advanced significantly by a number of x-ray crystallographic structures (reviewed in Refs. 3, 13, and 14), and several research groups have successfully used structure-based designs to synthesize active site-directed, selective PTP1B inhibitors (15-20). Most important, two groups have demonstrated recently that it is possible to develop compounds that are selective for PTP1B over the highly homologous T cell-PTP (21, 22), thereby lending support to the view that selective inhibitors, which discriminate between even closely related PTP...

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Protein tyrosine phosphatase-based therapeutics: lessons from PTP1B

Cited by 13 publications

References 84 publications

The anti‐inflammatory compound BAY‐11‐7082 is a potent inhibitor of protein tyrosine phosphatases

The anti‐inflammatory compound BAY‐11‐7082 is a potent inhibitor of protein tyrosine phosphatases

Regulation of Insulin Signaling through Reversible Oxidation of the Protein-tyrosine Phosphatases TC45 and PTP1B

Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β

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