Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids

Bobkova, Ekaterina V.; Liu, Wallace H.; Colayco, Sharon; Rascon, Justin; Vasile, Stefan; Gasior, Carlton; Critton, D.A.; Chan, Xochella; Dahl, Russell; Su, Ying; Sergienko, Eduard; Chung, Thomas D.Y.; Mustelin, Tomas; Page, Rebecca; Tautz, Lutz

doi:10.1021/ml100103p

Cited by 8 publications

(17 citation statements)

References 28 publications

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“…These interactions included hydrogen bonds between oxygen and nitrogen atoms of the heterocycle and the side chain of T106 of the substrate-binding loop (SB-loop), as well as favorable polar contacts between the bromine atom of the inhibitor and the ε -amino group of Lys105 in the HePTP SB-loop. We found similar interactions with residues of the SB-loop crucial for the selectivity of previously reported HePTP inhibitors [25]. In silico docking with the crystal structure of MKP-3 revealed a lack of such additional interactions with residues in the periphery of the catalytic pocket, perhaps explaining the substantially lower inhibitory activity of compound 1 against MKP-3.…”

Section: Resultssupporting

confidence: 80%

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Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation

Sergienko¹,

Xu²,

Liu³

et al. 2011

ACS Chem. Biol.

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The hematopoietic protein tyrosine phosphatase (HePTP) is implicated in the development of blood cancers through its ability to negatively regulate the mitogen-activated protein kinases (MAPKs) ERK1/2 and p38. Small-molecule modulators of HePTP activity may become valuable in treating hematopoietic malignancies such as T cell acute lymphoblastic leukemia (T-ALL) and acute myelogenous leukemia (AML). Moreover, such compounds will further elucidate the regulation of MAPKs in hematopoietic cells. Although transient activation of MAPKs is crucial for growth and proliferation, prolonged activation of these important signaling molecules induces differentiation, cell cycle arrest, cell senescence, and apoptosis. Specific HePTP inhibitors may promote the latter and thereby may halt the growth of cancer cells. Here, we report the development of a small molecule that augments ERK1/2 and p38 activation in human T cells, specifically by inhibiting HePTP. Structure-activity relationship analysis, in silico docking studies, and mutagenesis experiments reveal how the inhibitor achieves selectivity for HePTP over related phosphatases by interacting with unique amino acid residues in the periphery of the highly conserved catalytic pocket. Importantly, we utilize this compound to show that pharmacological inhibition of HePTP not only augments, but also prolongs activation of ERK1/2 and, especially, p38. Moreover, we present similar effects in leukocytes from mice intraperitoneally injected with the inhibitor at doses as low as 3 mg/kg. Our results warrant future studies with this probe compound that may establish HePTP as a new drug target for acute leukemic conditions.

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Section: Resultssupporting

confidence: 80%

“…Specific small molecule modulators of HePTP activity have only recently been described [25,26]. Such compounds are thought to augment ERK1/2 and p38 activation and may cause a sustained hyperactivation of these MAPKs.…”

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confidence: 99%

Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation

Sergienko¹,

Xu²,

Liu³

et al. 2011

ACS Chem. Biol.

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“…To identify DUSP3 inhibitors, we employed high-throughput screening (HTS), using a colorimetric phosphatase assay with p -nitrophenolphosphate (pNPP) as substrate, and screened 291,018 drug-like molecules. 24 Of the 1,524 primary HTS hits (≥50% inhibition), 1,048 compounds were available from BioFocus DPI and ordered for confirmatory assays. The hits were tested in two reconfirmation single-dose screens in triplicate, using both the primary colorimetric assay and an orthogonal fluorescent assay with 3-O-methylfluorescein phosphate (OMFP) as substrate.…”

Section: Resultsmentioning

confidence: 99%

Dual-Specificity Phosphatase 3 Deficiency or Inhibition Limits Platelet Activation and Arterial Thrombosis

Musumeci¹,

Kuijpers²,

Gilio³

et al. 2015

Circulation

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Background A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. Better understanding of the molecular mechanisms leading to platelet activation is of importance for the development of improved therapies. Recently, protein tyrosine phosphatases (PTPs) have emerged as critical regulators of platelet function. Methods and Results This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated through the collagen receptor glycoprotein VI (GPVI) and the C-type lectin-like receptor 2 (CLEC-2). DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism, compared to wild-type mice, and showed severely impaired thrombus formation upon ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of PLCγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen and CLEC-2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. Conclusions DUSP3 plays a selective and essential role in collagen- and CLEC-2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a PTP, implicated in platelet signaling, has been targeted with a small-molecule drug.

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“…Compound 20 (Fig. 5) was discovered from a counter screen of hit molecules identified for VHR in a high‐throughput screen of compound collections in the Molecular Library Probe Production Center Network [78]. Compound 20 contains a 2H‐thiazolo[3,2‐α]pyrimidin‐3(5H)‐one core structure with a phenoxyacetic acid headgroup, and exhibits an IC 50 of 1.0 μ m for HePTP, showing 19.5‐ and 42‐fold selectivity over VHR and MKP‐3, respectively.…”

Section: Small Molecule Ptp Inhibitorsmentioning

confidence: 99%

Small molecule tools for functional interrogation of protein tyrosine phosphatases

et al. 2012

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The importance of protein tyrosine phosphatases (PTPs) in the regulation of cellular signaling is well established. Malfunction of PTP activity is also known to be associated with cancer, metabolic syndromes, autoimmune disorders, neurodegenerative and infectious diseases. However, a detailed understanding of the roles played by the PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific small molecule agents. In addition, the therapeutic benefits of modulating this target class are underexplored due to lack of suitable chemical probes. Potent and specific PTP inhibitors could significantly facilitate functional analysis of the PTPs in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. We will highlight the current challenges and opportunities in developing PTP-specific small molecule agents. We will also review available selective small molecule inhibitors developed for a number of PTPs, including PTP1B, TC-PTP, SHP2, Lyp, HePTP, CD45, PTPβ, PTPγ, PTPRO, VHR, MKP-1, MKP-3, Cdc25, YopH, mPTPA, and mPTPB.

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Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids

Cited by 8 publications

References 28 publications

Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation

Inhibition of Hematopoietic Protein Tyrosine Phosphatase Augments and Prolongs ERK1/2 and p38 Activation

Dual-Specificity Phosphatase 3 Deficiency or Inhibition Limits Platelet Activation and Arterial Thrombosis

Small molecule tools for functional interrogation of protein tyrosine phosphatases

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