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  • Review Article
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Protein tyrosine phosphatase 1B inhibitors for diabetes

Nature Reviews Drug Discovery volume 1, pages 696–709 (2002)Cite this article

Key Points

  • Obesity and type 2 diabetes have become epidemic medical problems and will cause significant morbidity and mortality if new therapeutic agents cannot be brought forward.

  • Protein tyrosine phosphatase 1B (PTP1B) has been shown to be involved in the negative regulation of both insulin and leptin action at the in vitro, ex vivo and in vivo levels. A growing body of human genetic data also support the hypothesis that PTP1B has an important role in insulin signalling and possibly in obesity in humans.

  • PTP1B has been implicated in diabetes and obesity in knockout-mouse studies on a normal background. When crossed onto ob/ob mice, improvement in blood glucose and obesity is seen. When Ptp1b antisense oligonucleotides are administered in vivo to ob/ob mice, normalized blood glucose levels are obtained. Insulin sensitivity is improved at the cellular level.

  • PTP1B is tractable to structure-based drug design, and the crystal structure is well known. Recently, the crystal structure of the closely related T-cell protein tyrosine phosphatase (TCPTP) has become available, raising the possibility for designing selective inhibitors.

  • Potent (Ki values in the nM range) inhibitors of PTP1B are known, and oxamic acids are a common structural motif found in these compounds. The high polar surface area (PSA) and charge of this functionality make further optimization difficult, and an intense search to uncover phosphotyrosine mimetics with improved physico-chemical properties is in progress.

  • Pro-drugs of the oxamic acids and replacement of the acid functionality with isosteric functional groups might provide compounds with improved physico-chemical properties.

  • Lipophilic compounds have been reported — one of the two reported structures seems to be a competitive inhibitor of PTP1B and the other does not. This highlights the need for a clear understanding of the mechanism of inhibition and an understanding of the kinetics of compounds.

Abstract

Increased incidence of type 2 diabetes mellitus and obesity has elevated the medical need for new agents to treat these disease states. Resistance to the hormones insulin and leptin are hallmarks of both type 2 diabetes and obesity. Drugs that can ameliorate this resistance should be effective in treating type 2 diabetes and possibly obesity. Protein tyrosine phosphatase 1B (PTP1B) is thought to function as a negative regulator of insulin and leptin signal transduction. This article reviews PTP1B as a novel target for type 2 diabetes, and looks at the challenges in developing small-molecule inhibitors of this phosphatase.

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Figure 1: Type 2 diabetes disease-state continuum and regulation of the leptin and insulin signalling pathways by PTP1B.
Figure 2: Key aspects of the PTP1B X-ray crystal structure.
Figure 3: PTP1B binds phosphotyrosine in the active site and also in an adjacent site.
Figure 4: The YRD motif provides an opportunity for selective PTP inhibition.
Figure 5: Gly259 allows access to the adjacent phosphotyrosine-binding site in PTP1B.
Figure 6: The X-ray crystal structures of PTP1B and TCPTP.
Figure 7: PTP1B inhibitors: difluoromethylene phosphonates.
Figure 8: PTP1B inhibitors: 2-carbomethoxybenzoic acids.
Figure 9: PTP1B inhibitors: 2-oxalylaminobenzoic acids.
Figure 10: PTP1B inhibitors: lipophilic compounds.
Figure 11: Examples of slow- and fast-binding inhibition.
Figure 12: The physico-chemical properties of PTP1B inhibitors.

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References

  1. Zimmet, P., Alberti, K. G. M. M. & Shaw, J. Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001).An excellent overview of the epidemiology of diabetes.

    CAS  PubMed  Google Scholar 

  2. Sinha, R. et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N. Engl. J. Med. 346, 802–810 (2002).

    CAS  PubMed  Google Scholar 

  3. Rocchini, A. P. Childhood obesity and a diabetes epidemic. N. Engl. J. Med. 346, 854–855 (2002).

    PubMed  Google Scholar 

  4. Dunstan, D. W. et al. The rising prevalence of diabetes and impaired glucose tolerance. The Australian diabetes, obesity and lifestyle study. Diabetes Care 25, 829–834 (2002).

    PubMed  Google Scholar 

  5. Groop, L. & Orho-Melander, M. The dysmetabolic syndrome. J. Int. Med. 250, 105–120 (2001).

    CAS  Google Scholar 

  6. Poitout, V. & Robertson, P. R. Minireview: secondary β-cell failure in type 2 diabetes – a convergence of glucotoxity and lipotoxicity. Endocrinology 143, 339–342 (2002).

    CAS  PubMed  Google Scholar 

  7. Weyer, C., Tartanni, P. A., Bogardus, C. & Pratley, R. E. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 24, 89–94 (2001).

    CAS  PubMed  Google Scholar 

  8. Stumvoll, M., Fritsche, A. & Haring, H. U. Clinical characterization of insulin secretion as the basis for genetic analyses. Diabetes 51 (Suppl. 1), S122–S129 (2002).

    CAS  PubMed  Google Scholar 

  9. Uusitupa, M. et al. The Finnish Diabetes Prevention Study. Br. J. Nutr. 83 (Suppl. 1), S137–S142 (2000).

    CAS  PubMed  Google Scholar 

  10. The Diabetes Prevention Study Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

  11. Heine, R. J. & Dekker, J. M. Beyond postprandial hyperglycaemia: metabolic factors associated with cardiovascular disease. Diabetologia 45, 461–475 (2002).

    CAS  PubMed  Google Scholar 

  12. Marx, J. Unraveling the causes of diabetes. Science 296, 686–689 (2002).

    CAS  PubMed  Google Scholar 

  13. Saltiel, A. R. & Kahn, C. R. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).An excellent overview of metabolic insulin signal transduction.

    CAS  PubMed  Google Scholar 

  14. Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. & Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nature Neurosci. 5, 566–572 (2002).This article shows the role of the insulin receptor at the level of the CNS.

    CAS  PubMed  Google Scholar 

  15. Saltiel, A. R. & Pessin, J. E. Insulin signaling pathways in time and space. Trends Cell Biol. 12, 65–71 (2002).

    CAS  PubMed  Google Scholar 

  16. Bryant, N. J., Govers, R. & James, D. E. Regulated transport of the glucose transporter GLUT4. Nature Rev. Mol. Cell Biol. 3, 267–277 (2002).

    CAS  Google Scholar 

  17. Smith, U. Impaired ('diabetic') insulin signaling and action occur in fat cells long before glucose intolerance – is insulin resistance initiated in the adipose tissue? Int. J. Obes. Relat. Metab. Disord. 26, 897–904 (2002).

    CAS  PubMed  Google Scholar 

  18. Ostman, A. & Bohmer, F. D. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 11, 258–266 (2001).

    CAS  PubMed  Google Scholar 

  19. Cheng, A., Dube, N., Gu, F. & Tremblay, M. L. Coordinated action of protein tyrosine phosphatases in insulin signal transduction. Eur. J. Biochem. 269, 1050–1059 (2002).

    CAS  PubMed  Google Scholar 

  20. Goldstein, B. J., Bittner-Kowalczyk, A., White, M. F. & Harbeck, M. Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by protein-tyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the GRB2 adaptor protein. J. Biol. Chem. 275, 4283–4289 (2000).

    CAS  PubMed  Google Scholar 

  21. Wu, X. et al. Depot-specific variation in protein-tyrosine phosphatase activities in human omental and subcutaneous adipose tissue: a potential contribution to differential insulin sensitivity. J. Clin. Endocrinol. Metab. 86, 5973–5980 (2001).

    CAS  PubMed  Google Scholar 

  22. Cheung, A. et al. Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus. J. Lab. Clin. Med. 134, 115–123 (1999).

    CAS  PubMed  Google Scholar 

  23. Forsell, P. K. A. L., Boie, Y., Montalibet, J., Collins, S. & Kennedy, B. P. Genomic characterization of the human and mouse protein tyrosine phosphatase-1B genes. Gene 260, 145–153 (2000).

    CAS  PubMed  Google Scholar 

  24. Mok, A. et al. A single nucleotide polymorphism in protein tyrosine phosphatase PTP1B is associated with protection from diabetes or impaired glucose tolerance in Oji–Cree. J. Clin. Endocrinol. Metab. 87, 724–727 (2002).

    CAS  PubMed  Google Scholar 

  25. Di Paola, R. et al. A variation in 3′UTR of hPTP1B increases specific gene expression and associates with insulin resistance. Am. J. Hum. Genet. 70, 806–812 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Echwald, S. M. et al. A P387L variant in protein tyrosine phosphatase-1B (PTP1B) is associated with type 2 diabetes and impaired serine phosphorylation of PTP1B in vitro. Diabetes 51, 1–6 (2002).

    CAS  PubMed  Google Scholar 

  27. Goldstein, B. J. Protein tyrosine phosphatase 1B (PTP1B): a novel therapeutic target for type 2 diabetes mellitus, obesity and related states of insulin resistance. Curr. Drug Targets Immune Endocr. Metab. Disord. 1, 265–275 (2001).

    CAS  Google Scholar 

  28. Ukkola, O. & Santaniemi, M. Protein tyrosine phosphatase 1B: a new target for the treatment of obesity and associated co-morbidities. J. Int. Med. 251, 467–475 (2002).References 27 and 28 review the importance of PTP1B in insulin signalling.

    CAS  Google Scholar 

  29. Egawa, K. et al. Protein-tyrosine phosphatase-1B negatively regulates insulin signaling in l6 myocytes and Fao hepatoma cells. J. Biol. Chem. 276, 10207–10211 (2001).

    CAS  PubMed  Google Scholar 

  30. Chen, H. et al. Protein-tyrosine phosphatases PTP1B and SYP are modulators of insulin-stimulated translocation of GLUT4 in transfected rat adipose cells. J. Biol. Chem. 272, 8026–8031 (1997).

    CAS  PubMed  Google Scholar 

  31. Venable, C. L. et al. Overexpression of protein-tyrosine phosphatase-1B in adipocytes inhibits insulin-stimulated phosphoinositide 3-kinase activity without altering glucose transport or Akt/Protein kinase B activation. J. Biol. Chem. 275, 18318–18326 (2000).

    CAS  PubMed  Google Scholar 

  32. Mahadev, K. et al. Hydrogen peroxide generated during cellular insulin stimulation is integral to activation of the distal insulin signaling cascade in 3T3-L1 adipocytes. J. Biol. Chem. 276, 48662–48669 (2001).

    CAS  PubMed  Google Scholar 

  33. Tao, J., Malbon, C. C. & Wang, H. Insulin stimulates tyrosine phosphorylation and inactivation of protein tyrosine phosphatase 1B in vivo. J. Biol. Chem. 276, 29520–29525 (2001).

    CAS  PubMed  Google Scholar 

  34. Salmeen, A., Andersen, J. N., Myers, M. P., Tonks, N. K. & Barford, D. Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol. Cell 7, 615–621 (2001).

    Google Scholar 

  35. Barford, D. The mechanism of protein kinase regulation by protein phosphatases. Biochem. Soc. Trans. 29, 385–391 (2001)

    CAS  PubMed  Google Scholar 

  36. Xie, L., Zhang, Y. L. & Zhang, Z. Y. Design and characterization of an improved protein tyrosine phosphatase substrate-trapping mutant. Biochemistry 41, 4032–4039 (2002).

    CAS  PubMed  Google Scholar 

  37. Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771–47774 (2001).

    CAS  PubMed  Google Scholar 

  38. Haj, F. G., Verveer, P. J., Squire, A., Neel, B. G. & Bastiaens, P. I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708–1711 (2002).

    CAS  PubMed  Google Scholar 

  39. Gill, G. N. A pit stop at the ER. Science 295, 1654–1655 (2002).Reference 39 is a commentary about reference 38 that brings into perspective how PTP1B might have roles in regulating various RTKs.

    CAS  PubMed  Google Scholar 

  40. Dadke, S. & Chernoff, J. Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains. Biochem. J. 364, 377–383 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    CAS  PubMed  Google Scholar 

  42. Klaman, L. D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell. Biol. 20, 5479–5489 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kaszubska, W. et al. The role of PTP1B in leptin signalling. Keystone Symposia: Diabetes Mellitus: Molecular Mechanisms, Genetics and New Therapies Jan 10–16 226, 81 (2002).PTP1B has been implicated in negatively regulating insulin signal transduction, and this role is extended to include negative regulation of leptin signal transduction.

    Google Scholar 

  44. Zabolotny, J. M. et al. PTP1B regulates leptin signal transduction in vivo. Dev. Cell 2, 489–495 (2002).

    CAS  PubMed  Google Scholar 

  45. Cook, W. S. & Unger, R. H. Protein tyrosine phosphatase 1B: a potential leptin resistance factor of obesity. Dev. Cell 2, 385–387 (2002).

    CAS  PubMed  Google Scholar 

  46. Cheng, A. et al. Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev. Cell 2, 497–503 (2002).

    CAS  PubMed  Google Scholar 

  47. Zinker, B. A. et al. Reduction of protein tyrosine phosphatase 1B normalizes glucose and improves insulin sensitivity in diabetic mice. Proc. Natl Acad. Sci. USA 99, 11357–11362 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tonks, N. K., Diltz, C. D. & Fischer, E. H. Purification of the major protein-tyrosine phosphatases of human placenta. J. Biol. Chem. 263, 6722–6730 (1988).

    CAS  PubMed  Google Scholar 

  49. Barford, D., Flint, A. J. & Tonks, N. K. Crystal structure of human protein tyrosine phosphatase 1B. Science 263, 1397–1404 (1994).

    CAS  PubMed  Google Scholar 

  50. Jia, Z., Barford, D., Flint, A. J. & Tonks, N. K. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268, 1754–1758 (1998).

    Google Scholar 

  51. Groves, M. R., Yao, Z. J., Roller, P. P., Burke, T. R. Jr & Barford, D. Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics. Biochemistry 37, 17773–17783 (1998).

    CAS  PubMed  Google Scholar 

  52. Pannifer, A. D. B., Flint, A. J., Tonks, N. K. & Barford, D. Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by X-ray crystallography. J. Biol. Chem. 273, 10454–10462 (1998).

    CAS  PubMed  Google Scholar 

  53. Puius, Y. A. et al. Identification of a second aryl phosphate binding site in protein-tyrosine phosphatase 1B: a paradigm for inhibitor design. Proc. Natl Acad. Sci. USA 94, 13420–13425 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Hadjuk, P. J., Meadows, R. P. & Fesik, S. W. Discovering high affinity ligands for proteins. Science 278, 497–499 (1997).

    Google Scholar 

  55. Iversen, L. F. et al. Structure based design of a low molecular weight, non-phosphorous, non-peptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B. J. Biol. Chem. 275, 10300–10307 (2000).This paper describes the structure-based design of PTP1B inhibitors.

    CAS  PubMed  Google Scholar 

  56. Asante-Appiah, E. et al. The YRD motif is a major determinant of substrate and inhibitor specificity in T-cell protein-tyrosine phosphatase. J. Biol. Chem. 276, 26036–26043 (2001).

    CAS  PubMed  Google Scholar 

  57. Peters, G. H. et al. Residue 259 is a key determinant of substrate specificity of protein-tyrosine phosphatases 1B and α. J. Biol. Chem. 275, 18201–18209 (2000).

    CAS  PubMed  Google Scholar 

  58. Iversen, L. F. et al. Steric hindrance as a basis for structure-based design of selective inhibitors of protein tyrosine phosphatases. Biochemistry 40, 14812–14820 (2001).

    CAS  PubMed  Google Scholar 

  59. Iversen, L. F. et al. Structure determination of T cell protein-tyrosine phosphatase. J. Biol. Chem. 277, 19982–19990 (2002).

    CAS  PubMed  Google Scholar 

  60. Ibarra-Sanchez, M. D. et al. Murine embryonic fibroblasts lacking TC-PTP display delayed G1 phase through defective NF-κB activation. Oncogene 20, 4728–4739 (2001).

    CAS  PubMed  Google Scholar 

  61. You-Ten, K. E. et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J. Exp. Med. 18, 683–693 (1997).A review of PTP inhibitors from a medicinal chemistry perspective that provides a detailed analysis of the inhibitors identified so far.

    Google Scholar 

  62. Blaskovitch, M. A. & Kim, H.-O. Recent advances in discovery and development of protein tyrosine phosphatase inhibitors. Expert Opin. Ther. Patents 12, 871–905 (2002).

    Google Scholar 

  63. Burke, T. R., Kole, H. K. & Roller, P. P. Potent inhibition of insulin receptor dephosphorylation by a hexamer peptide containing the phosphotyrosyl mimetic F2Pmp. Biochem. Biophys. Res. Commun. 204, 129–134 (1994).

    CAS  PubMed  Google Scholar 

  64. Burke, T. R. Jr et al. Small molecule interactions with protein-tyrosine phosphatase PTP1B and their use in inhibitor design. Biochemistry 35, 15989–15996 (1996).

    CAS  PubMed  Google Scholar 

  65. Taing, M. et al. Potent and highly selective inhibitors of the protein tyrosine phosphatase 1B. Biochemistry 38, 3793–3803 (1999).

    CAS  PubMed  Google Scholar 

  66. Jia, Z. et al. Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J. Med. Chem. 44, 4584–4594 (2001).

    CAS  PubMed  Google Scholar 

  67. Bayly, C. & Ohkubo, M. Sulfur substituted aryldifluoromethylphosphonic acids as PTP1B inhibitors. Patent WO 01/70754 (2001).

  68. Leblanc, Y., Dufresne, C., Gauthier, J. Y. & Young, R. Aromatic phosphonates as protein tyrosine phosphatase 1B (PTP1B) inhibitors. Patent WO 01/46204 (2001).

  69. Shen, K. et al. Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. J. Biol. Chem. 276, 47311–47319 (2001).

    CAS  PubMed  Google Scholar 

  70. Leblanc, Y., Dufresne, C., Roy, P. & Wang, Z. Phosphonic and carboxylic acid derivatives as inhibitors of protein tyrosine phosphatase-1B. Patent WO 00/69889 (2000).

  71. Burke T. R. Jr et al. Enantioselective synthesis of nonphosphorous-containing phosphotyrosyl mimetics and their use in the preparation of tyrosine phophatase inhibitory peptides. Tetrahedron 54, 9981–9994 (1998).

    CAS  Google Scholar 

  72. Bleasdale, J. E. et al. Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action. Biochemistry 40, 5642–5654 (2001).

    CAS  PubMed  Google Scholar 

  73. Larsen, S. D. et al. Synthesis and biological activity of a novel class of small molecular weight peptidomimetic competitive inhibitors of protein tyrosine phosphatase 1B. J. Med. Chem. 45, 598–622 (2002).

    CAS  PubMed  Google Scholar 

  74. Liljebris, C., Larsen, S. D., Ogg, D., Palazuk, B. J. & Bleasedale, J. E. Investigation of potential bioisosteric replacements for the carboxyl groups of peptidomimetic inhibitors of protein tyrosine phosphatase 1B: identification of a tetrazole-containing inhibitor with cellular activity. J. Med. Chem. 45, 1785–1798 (2002).This article describes the production of inhibitors with improved physico-chemical properties.

    CAS  PubMed  Google Scholar 

  75. Andersen, et al. 2-(Oxalylamino)benzoic acid is a general, competitive inhibitor of protein tyrosine phosphatases. J. Biol. Chem. 275, 7101–7108 (2000).

    CAS  PubMed  Google Scholar 

  76. Iversen, L. F. et al. Structure based design of a low molecular weight, non-phosphorous, non-peptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B. J. Biol. Chem. 275, 10300–10307 (2000).

    CAS  PubMed  Google Scholar 

  77. Andersen, H. S. Method of inhibiting protein tyrosine phosphatase 1B and/or T-cell protein tyrosine phosphatase and/or other PTPases with Asp residue at position 48. Patent WO 01/17516 (2001).

  78. Lui, G. et al. Discovery of competitive, potent, and selective protein tyrosine phosphatase 1B inhibitors. 223rd American Chemical Society National Meeting, Orlando, Florida, April 7–11, 2002 MEDI–002 (2002).

    Google Scholar 

  79. Wrobel, J. et al. PTP1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel 11-arylbenzo[b]naphtha[2,3-d]furans and 11-arylbenzo[b]naphto[2,3-d]thiophenes. J. Med. Chem. 42, 3199–3202 (1999).

    CAS  PubMed  Google Scholar 

  80. Reuters Business Report. (10 Jun 2002).

  81. McGovern, S. L., Caselli, E., Grigorieff, N. & Shoichet, B. K. A common mechanism underlying promiscuous inhibitors from virtual and high throughput screening. J. Med. Chem. 45, 1712–1722 (2002).

    CAS  PubMed  Google Scholar 

  82. Doman, T. N. et al. Molecular docking and high throughput screening for novel inhibitors of protein tyrosine phosphatase-1B. J. Med. Chem. 45, 2213–2221 (2002).The establishment of robust assay systems to determine activity and mechanism.

    CAS  PubMed  Google Scholar 

  83. Lubben, T., Clampit, J., Stashko, M., Trevillyan, J. & Jirousek, M. R. in Current Protocols in Pharmacology Vol. 8 Ch. 3 (Emma, S. I. et al.) 1–18 (John Wiley, New York, 2001).

    Google Scholar 

  84. Cornish-Bowden, A. Fundamentals of Enzyme Kinetics (Portland Press, London, 1995).

    Google Scholar 

  85. Copeland, R. A. Enzymes: a Practical Introduction to Structure, Mechanism, and Data Analysis 2nd edn (Wiley–VCH, New York, 2000).

    Google Scholar 

  86. Bieth, J. G. Theoretical and practical aspects of proteinase inhibition kinetics. Methods Enzymol. 248, 59–84 (1995).

    CAS  PubMed  Google Scholar 

  87. Zhang, Y. L., Keng, Y. F., Zhao, Y., Wu, L. & Zhang, Z. Y. Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases. J. Biol. Chem. 273, 12281–12287 (1998).

    CAS  PubMed  Google Scholar 

  88. Lu, B. et al. Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4). J. Biol. Chem. 276, 35589–35598 (2001).

    CAS  PubMed  Google Scholar 

  89. Huyer, G. et al. Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J. Biol. Chem. 272, 843–851 (1997).

    CAS  PubMed  Google Scholar 

  90. Crans, D., Bunch, R. L. & Theisen, L. A. Interaction of trace levels of vanadium (IV) and vanadium (V) in biological systems. J. Am. Chem. Soc. 111, 7597–7607 (1989).

    CAS  Google Scholar 

  91. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 23, 3–25 (1997).

    CAS  Google Scholar 

  92. Palm, K., Stenberg, P., Luthman, K. & Artursson, P. Polar molecular surface properties predict the intestinal absorption of drugs in humans. Pharm. Res. 14, 568–571 (1997).

    CAS  PubMed  Google Scholar 

  93. Veber, D. F. et al. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 45, 2615–2623 (2002).

    CAS  PubMed  Google Scholar 

  94. Pei, Z. et al. (2R)-2-(2′,6′-dichloro-4′-dibenzo(b,d)furan-4″-ylphenoxy)-3-phenylpropanoic acid (A-321842) as a protein tyrosine phosphatase 1B (PTP1B) inhibitor with anti-diabetic effects in ob/ob mice. Diabetes 50 (Suppl. 1), 1524-P (2001).

    Google Scholar 

  95. Burkey, B. F. et al. Pharmacogenomic evaluation of a putative orally active PTP1B inhibitor using ob/ob mice reveals an alternative mechanism of action. Diabetes 51 (Suppl. 2), 138-OR (2002).

    Google Scholar 

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Acknowledgements

We apologize to colleagues for the many references we could not site due to space limitations. We thank A. Castro for collecting some of the data and J. Thomson, D. Vanderpool and J. Nelson for reading the manuscript.

Author information

Authors and Affiliations

  1. Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, 92121, California, USA

    Theodore O. Johnson, Jacques Ermolieff & Michael R. Jirousek

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  1. Theodore O. Johnson
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Correspondence to Michael R. Jirousek.

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DATABASES

LocusLink

ACC

EGF

GLUT4

GRB2

GSK3

IGF1

insulin

insulin receptor

IRS1

JAK2

LAR

leptin

leptin receptor

PDGF

PDK1

PI3K

PKB

PPAR-γ

PTP1B

rPTP-α

SHP2

STAT3

Stat3

TCPTP

VHR

Medscape DrugInfo

metformin

OMIM

type 2 diabetes mellitus

Glossary

OBESITY

In the United States, obesity is defined as having a body-mass index (BMI; the weight in kg divided by the height (in m) squared) ≥ 30 or BMI ≥ 27 with diabetes, hypertension or dyslipidaemia.

PANCREATIC ISLET

Islets of Langerhans, which are found in the pancreas, consist of insulin-producing β-cells, somatostatin-producing δ-cells, glucagon-producing α-cells and polypeptide-producing pp cells.

POSTPRANDIAL

The period of macronutrient absorption after a meal, usually considered to be two hours in length.

METABOLIC SYNDROME

The appearance of several metabolic disorders together. The World Health Organisation defines this as one of type 2 diabetes, impaired glucose tolerance or insulin resistance, in combination with two of the following presentations — hypertension, obesity, hypertriglyceridaemia or low HDL, or microalbuminuria.

GLUCOSE HOMEOSTASIS

The maintenance of glucose levels during fluctuating physiological pressures, such as eating, exercising, resting or disease.

PROTEIN TYROSINE PHOSPHATASE

An enzyme that removes phosphate from tyrosine residues in proteins.

OMENTAL FAT

Adipose tissue located in the omental, such as the viscera below the subcutaneous space.

OJI–CREE INDIANS

A Native North American tribe that lives in the Sandy Lake area of Canada. This population has an incidence of obesity-related type 2 diabetes or impaired glucose tolerance of ∼40%.

SINGLE-NUCLEOTIDE POLYMORPHISM

(SNP). A variation in a nucleotide in a gene that could result in altered gene function or altered protein function if it affects amino-acid coding.

LINKAGE DISEQUILIBRIUM

The association between a pair of alleles at closely linked loci that induces haplotype frequencies different than the product of the individual allele frequencies.

HDL CHOLESTEROL

High-density lipoprotein (HDL) that is associated with a high proportion of protein (48%) and low triglyceride (3%) and cholesterol (19%) — HDL density is 1.06–1.21 g ml−1.

ob/ob MOUSE

A homozygous mutation in the leptin gene located on chromosome 6 that causes the absence of functional leptin in the mouse strain C57BL/6J, producing a model of severe obesity with hyperphagia and diabetes.

ARYL PHOSPHATE

The phosphate group attached at the 4-position of the phenyl group in tyrosine.

NUCLEOPHILE

An atom that is attracted to the nucleus of another — in this case, the cysteine sulphur acts as a nucleophile and attacks the phosphotyrosine phosphorous atom.

HYDROPHOBIC

A molecular interaction that occurs in the absence of aqueous solvent or water.

SALT BRIDGE

The formation of an ionic-charge interaction between two molecules or between two regions of a molecule.

PEPTIDOMIMETIC

Mimicking a peptide–peptide interaction through a non-peptide bond or structure.

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Johnson, T., Ermolieff, J. & Jirousek, M. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1, 696–709 (2002). https://doi.org/10.1038/nrd895

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