Synthesis of exo-affinity labeling agents of protein tyrosine phosphatase non-receptor type 1

2015 ◽  
Author(s):  
◽  
Roman Hillebrand
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Allyl Isothiocyanate ◽  
Negative Regulator ◽  
Cancer Drug ◽  
University Of Missouri ◽  
Protein Tyrosine ◽  
Wide Range ◽  
The University ◽  
Derivatives Of

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Protein-tyrosine phosphatase 1B (PTP1B) is a negative regulator in the insulin signaling cascade. A lot of research has focused on inhibiting PTP1B but with no success. Only one drug is currently in phase II clinical trials. We have developed a synthetic protocol to create a library of molecules that target residues outside the active site and covalently bind to the enzyme via close proximity alkylation. These molecules will be analyzed towards inactivation/inhibition capabilities. Tirapazamine is a hypoxia selective anti-cancer drug. New derivatives of Tirapazamine are sought after. We have analyzed and optimized Suzuki-Miyaura and Buchwald-Hartwig couplings reactions towards new derivatives of Tirapazamine. Allyl isothiocyanate (AITC) is a phytochemical that can be found in cruciferous vegetables and has received interest due to beneficial health effects. During our analyses of AITC towards inactivation of PTP1B we noticed the surprising absence of the isothiocyanate carbon in 13C NMR spectra. Calculations show that the absence is due to the facile change of the N-hybridization in the wide range of 120 less than 180 bond angles in AITC.

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

Synthesis and properties of small molecules designed to covalently capture native and oxidized forms of protein tyrosine phosphatase 1B (PTP1B)

2016 ◽  
Author(s):  
◽  
Kasi Viswanatharaju Ruddraraju
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Tyrosine Phosphatase ◽  
Covalent Modification ◽  
Affinity Labeling ◽  
Protein Tyrosine Phosphatase 1B ◽  
University Of Missouri ◽  
Protein Tyrosine ◽  
Enzyme Active Site ◽  
Carbon Nucleophiles

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Protein tyrosine phosphatase 1B (PTP1B) is a validated target for the treatment of type 2 diabetes and obesity. The discovery of selective inhibitors with drug-like properties has proven to be challenging because there are [about]80 PTP family members that share a similar and positively charged active site. To overcome these challenges, we have pursued two novel approaches for the covalent inactivation of PTP1B. Exo-affinity labeling agents exploit covalent reactions with amino acids outside the enzyme active site to gain both affinity and selectivity. We prepared several affinity labeling agents using a 12-step convergent synthesis. Enzyme assays revealed that some of these agents are capable of inactivating the enzyme by covalent modification. In another project, we prepared a low molecular weight mimic of the oxidized form of PTP1B that is generated in cells, during insulin signaling events. Seeking molecules capable of covalent capture of oxidized PTP1B, we treated this chemical model with several carbon nucleophiles, such as 1,3-diketones and sulfone-stabilized carbon anions. These carbon nucleophiles readily reacted with the model compound, under mild conditions to give stable adducts. Inactivation experiments revealed that 1,3-diketones are capable of inactivating the oxidized PTP1B at micromolar concentrations.

scholarly journals Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis

2017 ◽  
Vol 131 (20) ◽  
pp. 2489-2501 ◽  
Author(s):  
Dawn Thompson ◽  
Nicola Morrice ◽  
Louise Grant ◽  
 Samantha Le Sommer ◽  
Emma K. Lees ◽  
...  
Keyword(s):  
Mouse Model ◽  
Atherosclerotic Plaque ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Plaque Formation ◽  
Negative Regulator ◽  
Protein Tyrosine Phosphatase 1B ◽  
Cvd Risk ◽  
Protein Tyrosine ◽  
Atherosclerotic Plaque Formation

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR−/− mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR−/− mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

scholarly journals Regulation of Microtubule Nucleation in Mouse Bone Marrow-Derived Mast Cells by Protein Tyrosine Phosphatase SHP-1

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 345 ◽  
Author(s):  
Klebanovych ◽  
Sládková ◽  
Sulimenko ◽  
Vosecká ◽  
Čapek ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cells ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Negative Regulator ◽  
Mast Cell Activation ◽  
Mouse Bone Marrow ◽  
Microtubule Nucleation ◽  
Protein Tyrosine

The antigen-mediated activation of mast cells initiates signaling events leading to their degranulation, to the release of inflammatory mediators, and to the synthesis of cytokines and chemokines. Although rapid and transient microtubule reorganization during activation has been described, the molecular mechanisms that control their rearrangement are largely unknown. Microtubule nucleation is mediated by γ-tubulin complexes. In this study, we report on the regulation of microtubule nucleation in bone marrow-derived mast cells (BMMCs) by Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1; Ptpn6). Reciprocal immunoprecipitation experiments and pull-down assays revealed that SHP-1 is present in complexes containing γ-tubulin complex proteins and protein tyrosine kinase Syk. Microtubule regrowth experiments in cells with deleted SHP-1 showed a stimulation of microtubule nucleation, and phenotypic rescue experiments confirmed that SHP-1 represents a negative regulator of microtubule nucleation in BMMCs. Moreover, the inhibition of the SHP-1 activity by inhibitors TPI-1 and NSC87877 also augmented microtubule nucleation. The regulation was due to changes in γ-tubulin accumulation. Further experiments with antigen-activated cells showed that the deletion of SHP-1 stimulated the generation of microtubule protrusions, the activity of Syk kinase, and degranulation. Our data suggest a novel mechanism for the suppression of microtubule formation in the later stages of mast cell activation.

Phosphonate monoesters on a thiacalix[4]arene framework as potential inhibitors of protein tyrosine phosphatase 1B

2015 ◽  
Vol 13 (33) ◽  
pp. 8803-8806 ◽  
Author(s):  
Viacheslav V. Trush ◽  
Sergiy G. Kharchenko ◽  
Vsevolod Yu. Tanchuk ◽  
Vitaly I. Kalchenko ◽  
Andriy I. Vovk
Keyword(s):  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Methylphosphonic Acid ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Potential Inhibitors ◽  
Derivatives Of

Monoester derivatives of thiacalix[4]arene tetrakis(methylphosphonic) acid were found to be capable of inhibiting protein tyrosine phosphatase 1B. In addition, these compounds can strongly bind to human serum albumin.

scholarly journals Protein-tyrosine Phosphatase Shp-1 Is a Negative Regulator of IL-4- and IL-13-dependent Signal Transduction

1998 ◽  
Vol 273 (51) ◽  
pp. 33893-33896 ◽  
Author(s):  
S. Jaharul Haque ◽  
Phyllis Harbor ◽  
Mina Tabrizi ◽  
Taolin Yi ◽  
Bryan R. G. Williams
Keyword(s):  
Signal Transduction ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Protein Tyrosine ◽  
Dependent Signal

Deletion of the Protein Tyrosine Phosphatase Gene PTPN2 in T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 141-141
Author(s):  
Maria Kleppe ◽  
Idoya Lahortiga ◽  
Tiama El Chaar ◽  
Kim De Keersmaecker ◽  
Nicole Mentens ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Protein Tyrosine Phosphatase ◽  
Lymphoblastic Leukemia ◽  
Tyrosine Phosphatase ◽  
Janus Kinase ◽  
Negative Regulator ◽  
Aberrant Expression ◽  
Protein Tyrosine ◽  
Knock Down

Abstract Abstract 141 Introduction: T-cell lymphoblastic leukemia (T-ALL) arises from clonal expansion of a lymphoid progenitor that has undergone stepwise alteration at distinct stages of differentiation. It is suggested that a set of cooperative mutations that affect different pathways are required before thymocytes become fully malignant. Despite major improvements in our understanding of the molecular genetics of T-ALL, the underlying mechanisms that lead to the abnormal proliferation and enhanced survival of the leukemic cells remain largely unknown. Results: Array CGH analysis revealed an acquired homozygous microdeletion at chromosome 18p11 in 6 % of T-ALL cases. The deleted region was only 125 kb in size and restricted to the PTPN2 (protein tyrosine phosphatase, non-receptor type 2) locus. PTPN2 encodes an intracellular non-transmembrane tyrosine-specific phosphatase that functions as a negative regulator of a variety of signaling proteins including several members of the janus kinase (JAK) and of signal transducer and activator of transcription (STAT) families, growth factor receptors and SRC family kinases. Homozygous deletion of PTPN2 was specifically found in cases with aberrant expression of the TLX1 transcription factor, with two cases also harboring the NUP214-ABL1 fusion. Analysis of additional TLX1 positive cases by quantitative PCR identified loss of one copy of PTPN2 in 5 out of 20 cases. No mutations were detected in the coding region of PTPN2. To determine the effect of loss of PTPN2 in T-cells, we downregulated the expression of PTPN2 using RNAi technology. siRNA mediated knock-down of PTPN2 affected activation of JAK1 associated cytokine receptors implicated in T-cell development. Ligand stimulation of IL7 and interferon gamma receptor resulted in an augmented and prolonged phosphorylation of JAK1 as well as downstream targets STAT1 and STAT5 in T-ALL cell lines with knock-down of PTPN2. In addition, knock- down of Ptpn2 sensitized the pro B-cell line Ba/F3 to transformation by wild type JAK1 confirming a clear relationship between loss of PTPN2 and JAK1 activation. Knock-down of PTPN2 expression also provided a proliferative advantage and reduced sensitivity to kinase inhibitors in lymphoblastic leukemia cell lines HSB-2 and ALL-SIL. Conclusion: In conclusion, our data provide genetic and functional evidence for a tumor suppressor role of PTPN2 in T-ALL and warrant testing of JAK inhibitors for the treatment of this specific subset of T-ALLs as well as further analysis of a potential negative impact of loss of PTPN2 on responsiveness to anti-cancer treatments. Disclosures: Ferrando: Merck, Pfizer: Research Funding.

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