Targeting the disordered C terminus of PTP1B with an allosteric inhibitor

Krishnan, Navasona; Koveal, Dorothy; Miller, Daniel; Xue, Bin; Akshinthala, S. Dipikaa; Kragelj, Jaka; Jensen, Malene Ringkjøbing; Gauss, Carla‐Maria; Page, Rebecca; Blackledge, Martin; Muthuswamy, Senthil K.; Peti, Wolfgang; Tonks, Nicholas K.

doi:10.1038/nchembio.1528

Cited by 309 publications

(392 citation statements)

References 44 publications

(54 reference statements)

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“…At reasonable doses, namely, 5 mg/kg, the compound blocks the growth of established breast tumors and prevents lung metastasis in a breast cancer model. 75 These studies not only fortify the hypothesis that PTP1N is a valuable therapeutic target but also illustrate an attractive molecular approach to PTP inhibition.…”

Section: Ptpn1mentioning

confidence: 90%

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New Approaches to Difficult Drug Targets: The Phosphatase Story

2017

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The drug discovery landscape is littered with promising therapeutic targets that have been abandoned because of insufficient validation, historical screening failures, and inferior chemotypes. Molecular targets once labeled as “undruggable” or “intractable” are now being more carefully interrogated, and while they remain challenging, many target classes are appearing more approachable. Protein tyrosine phosphatases represent an excellent example of a category of molecular targets that have emerged as druggable, with several small molecules and antibodies recently becoming available for further development. In this review, we examine some of the diseases that are associated with protein tyrosine phosphatase dysfunction and use some prototype contemporary strategies to illustrate approaches that are being used to identify small molecules targeting this enzyme class.

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Section: Ptpn1mentioning

confidence: 90%

“…Most notable has been the discovery of MSI-1438, which targets the disordered, noncatalytic, carboxy-terminus of PTPN1. 75 Binding of MSI-1438 locks PTPN1 in an inactive conformation and effectively blocks enzymatic activity. The compound inhibits HER2 signaling in vitro and in vivo.…”

Section: Ptpn1mentioning

confidence: 99%

New Approaches to Difficult Drug Targets: The Phosphatase Story

2017

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“…However, past efforts to develop drugs that target specific PTPs have been plagued by issues related to the bioavailability and selectivity of these compounds, as by the same research group (28 -/+ mice, which are a closer reflection of RTT in humans. In addition, PTP1B inhibitor-treated MECP2-deficient mice were subjected to distinct behavioral tests, including paw clasping, regression of motor skills, and pup gathering, to assess the effect of treatment on phenotypic symptoms.…”

Section: Ptps: Drugging the Undruggablementioning

confidence: 99%

“…(26). Notably, allosteric inhibition of PTPs has gained substantial traction recently, including allosteric inhibition of PTP1B (28). Previous highthroughput screening (HTS) efforts to find PTP inhibitors were mostly based on simple biochemical assays that used truncated PTPs and small pTyr mimics as substrates, a combination that favors the identification of hits that target the conserved active site.…”

Section: Ptp1b Inhibitors: Improving Symptoms and Survival In Rtt Animentioning

confidence: 99%

PTP1B: a new therapeutic target for Rett syndrome

Tautz¹

2015

J. Clin. Invest.

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C o m m e n t a r y Methyl-CpG-binding protein 2: linking epigenetics to neuronal functionOver 95% of classic Rett syndrome (RTT) cases are linked to mutations in a single gene that encodes methyl-CpG-binding protein 2 (MECP2) (1, 2), one of six mammalian methyl-CpG-binding proteins identified so far. These proteins specifically bind DNA methylated at the 5′ position of cytosine within cytosine-guanine (CpG) dinucleotide sequences, a process that constitutes an important gene-silencing mechanism in eukaryotes and is essential for viability (3). MECP2 dysfunction results in various neuropsychiatric disorders that include mild mental retardation, learning disabilities, autism spectrum disorders, and complex forms of severe mental retardation (1, 2). In RTT, numerous, mostly spontaneous mutations have been identified in MECP2 that result in a loss of MECP2 function. Several Mecp2-KO mouse models have been generated to investigate RTT pathology and to potentially identify and test new therapies (2). MECP2-deficient mice manifest many of the predominant characteristics of human RTT. The traditionally held belief is that the neurological and psychiatric features caused by RTT-associated failures that occur during brain development are irreversible; however, studies in MECP2-deficient mice suggest that normal brain function can be restored by reinstating MECP2 (4). These results are promising, because they suggest that it may be possible to improve neuronal function in patients with RTT. However, therapeutic approaches aimed at altering MECP2 levels in patients will likely require a more complex strategy, as both loss of MECP2 function and elevated MECP2 levels have deleterious neurological effects. Thus, current basic and clinical research has focused on identification of critical factors downstream of MECP2 that have altered expression or function and may directly cause neuronal defects in RTT. Candidate molecules include brainderived neurotrophic factor (BDNF) and IGF-1, both of which are currently the focus of many investigations (5-8). Approaches that elevate BDNF expression and those using BDNF mimetics have shown promising results in RTT animal models (9-12), while phase I clinical trials of recombinant IGF-1 treatment in patients with RTT have produced encouraging outcomes (13). PTP1B: linking MECP2 to insulin signalingSeveral lines of evidence suggest that RTT is associated with metabolic disorders. First, lipid metabolism is disturbed in both RTT mouse models, in which cholesterol levels are elevated in the brain (14), and in RTT patients, in whom plasma levels of cholesterol regulatory proteins are altered (15). Second, various studies found typical signs of insulin and leptin resistance as well as obesity in RTT animal models (16,17). Moreover, insulin resistance has also been reported in patients with RTT (18). In this issue, Krishnan and colleagues investigated the metabolic processes associated with RTT (19). The authors examined glucose metabolism and insulin signaling in male Mecp2 -/y and female Mecp2...

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“…PTP1B(1-321) is described in Ref. 16. YAP1 shRNA constructs in the pLKO1 vector were obtained from Addgene; plasmids 42540 and 42541 (17).…”

Section: Materials-growth Factor Reduced Matrigelmentioning

confidence: 99%

A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells

Ramesh

Krishnan

Muthuswamy

et al. 2015

Journal of Biological Chemistry

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Background:The role of protein-tyrosine phosphatases (PTP) in ERBB2 signaling is undefined. Results: Phosphatidic acid (PA) activated PTPD2; inhibition of PA production or PTPD2 expression attenuated ERBB2-mediated morphological changes in mammary epithelial cells. Conclusion: The PLD2-PTPD2 axis is required for ERBB2 signaling. Significance: PA-regulated PTPD2 activity is a novel, positive element of ERBB2 signaling, which may offer a new therapeutic strategy in breast cancer.

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Targeting the disordered C terminus of PTP1B with an allosteric inhibitor

Cited by 309 publications

References 44 publications

New Approaches to Difficult Drug Targets: The Phosphatase Story

New Approaches to Difficult Drug Targets: The Phosphatase Story

PTP1B: a new therapeutic target for Rett syndrome

A Novel Phosphatidic Acid-Protein-tyrosine Phosphatase D2 Axis Is Essential for ERBB2 Signaling in Mammary Epithelial Cells

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