The importance of PTPs in the regulation of cellular signaling is well established. In spite of the large number of PTPs identified to date and the emerging roles played by PTPs in human diseases, a detailed understanding of the role played by PTPs in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific agents. Such PTP-specific inhibitors could potentially serve as useful tools in determining the physiological significance of protein tyrosine phosphorylation in complex cellular signal transduction pathways and may constitute valuable therapeutics in the treatment of several human diseases. Despite the difficulties in obtaining such compounds, there are now several relatively specific inhibitors for PTP1B. It appears that significant differences exist within the active site and the immediate surroundings of various PTPs such that selective, tight-binding PTP inhibitors can be developed. In principle, an identical approach (i.e., to create bidentate inhibitors that could span both the active site and a unique adjacent peripheral site) used for PTP1B could also be employed to produce specific small-molecule inhibitors for all members of the PTP family that would enable the pharmacological modulation of selected signaling pathways for treatment of various diseases. Combinatorial solid-phase library synthesis is
Figure 4 Other PTP inhibitors.
finding wide applicability throughout the pharmaceutical industry, and, not surprisingly, this technique has begun to yield fruitful results in the area of PTP inhibitors.
Work in the author's laboratory was supported by Grants CA69202 and AI48506 from the National Institutes of Health, and by the G. Harold and Leila Y. Mathers Charitable Foundation.
1. Barford, D. (1999). Structural studies of reversible protein phosphorylation and protein phosphatases. Biochem. Soc. Trans. 27, 751-766.
2. Zhang, Z.-Y. (1998). Protein-tyrosine phosphatases: biological function, structural characteristics, and mechanism of catalysis. CRC Crit. Rev. Biochem. Mol. Biol. 33, 1-52.
3. Tonks, N. K. and Neel, B. G. (2001). Combinatorial control of the specificity of protein tyrosine phosphatases. Curr. Opin. Cell Biol. 2, 182-195.
4. Li, L. and Dixon, J. E. (2000). Form, function, and regulation of protein tyrosine phosphatases and their involvement in human diseases. Semin. Immunol. 12, 75-84.
5. Zhang, Z. -Y. (2001). Protein tyrosine phosphatases: prospects for therapeutics. Curr. Opin. Chem. Biol. 5, 416-423.
6. Guan, K. L. and Dixon, J. E. (1991). Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. J. Biol. Chem. 266, 17026-17030.
7. Zhang, Z.-Y. and Dixon, J. E. (1993). Active site labeling of the Yersinia protein tyrosine phosphatase: the determination of the pKa of the active site cysteine and the function of the conserved histidine 402. Biochemistry 32, 9340-9345.
8. Tonks, N. K., Diltz, C. D., and Fischer, E. H. (1988). Characterization of the major protein-tyrosine-phosphatases of human placenta. J. Biol. Chem. 263, 6731-6737.
9. Pot, D. A., Woodford, T. A., Remboutsika, E., Haun, R. S., and Dixon, J. E. (1991). Cloning, bacterial expression, purification, and characterization of the cytoplasmic domain of rat LAR, a receptor-like protein tyrosine phosphatase. J. Biol. Chem. 266, 19688-19696.
10. Myers, J. K. and Widlanski, T. S. (1993). Mechanism-based inactiva-tion of prostatic acid phosphatase. Science 262,1451-1453.
11. Wang, Q., Dechert, U., Jirik, F., and Withers, S. G. (1994). Suicide inactivation of human prostatic acid phosphatase and a phosphotyro-sine phosphatase. Biochem. Biophys. Res. Commun. 200, 577-583.
12. Taylor, W. P., Zhang, Z.-Y., and Widlanski, T. S. (1996). Quiescent affinity inactivators of protein tyrosine phosphatases. Bioorg. Med. Chem. 4, 1515-1520.
13. Arabaci, G., Guo, X.-C., Beebe, K. D., Coggeshall, K. M., and Pei, D. (1999). a-Haloacetophenone derivatives as photoreversible covalent inhibitors of protein tyrosine phosphatases. J. Am. Chem. Soc. 121, 5085-5086.
14. Schoenwaelder, S. M. and Burridge, K. (1999). Evidence for a calpeptin-sensitive protein-tyrosine phosphatase upstream of the small GTPase Rho. A novel role for the calpain inhibitor calpeptin in the inhibition of protein-tyrosine phosphatases. J. Biol. Chem. 274, 14359-14367.
15. Tamura, K., Southwick, E. C., Kerns, J., Rosi, K., Carr, B. I., Wilcox, C., and Lazo, J. S. (2000). Cdc25 inhibition and cell cycle arrest by a synthetic thioalkyl vitamin K analogue. Cancer Res. 60, 1317-1325.
16. Lee, S. R., Kwon, K. S., Kim, S. R., and Rhee, S. G. (1998). Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366-15372.
17. Denu, J. M. and Tanner, K. G. (1998). Specific and reversible inactiva-tion of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37, 5633-5642.
18. Barrett, W. C., DeGnore, J. P., Keng, Y.-F., Zhang, Z.-Y., Yim, M.-B., and Chock, P. B. (1999). Roles of superoxide radical anion in signal transduction mediated by reversible regulation of protein tyrosine phosphatase 1B. J. Biol. Chem. 274, 34543-34546.
19. Caselli, A., Chiarugi, P., Camici, G., Manao, G., and Ramponi, G. (1995). In vivo inactivation of phosphotyrosine protein phosphatases by nitric oxide. FEBS Lett. 374, 249-252.
20. Zhang, Z.-Y. (1995). Kinetic and mechanistic characterization of a mammalian protein tyrosine phosphatase, PTP1. J. Biol. Chem. 270, 11199-11204.
21. Stuckey, J. A., Schubert, H. L., Fauman, E., Zhang, Z.-Y., Dixon, J. E., and Saper, M. A. (1994). Crystal structure of Yersinia protein tyrosine phosphatase at 2.5 Ä and the complex with tungstate. Nature 370, 571-575.
22. Huyer, G., Liu, S., Kelly, J., Moffat, J., Payette, P., Kennedy, B., Tsaprailis, G., Gresser, M. J., and Ramachandran, C. (1997). Mechanism of inhibition of protein-tyrosine phosphatases by vanadate and pervanadate. J. Biol. Chem. 272, 843-851.
23. Denu, J. M., Lohse, D. L., Vijayalakshmi, J., Saper, M. A., and Dixon, J. E. (1996). Visualization of intermediate and transition-state structures in protein-tyrosine phosphatase catalysis. Proc. Natl. Acad. Sci. USA 93, 2493-2498.
24. Pannifer, A. D., Flint, A. J., Tonks, N. K., and Barford, D. (1998). Visualization of the cysteinyl-phosphate intermediate of a protein-tyrosine phosphatase by X-ray crystallography. J. Biol. Chem. 273, 10454-10462.
25. Zhang, M., Zhou, M., Van Etten, R. L., and Stauffacher, C. V. (1997). Crystal structure of bovine low molecular weight phosphotyrosyl phos-phatase complexed with the transition state analog vanadate. Biochemistry 36, 15-23.
26. Deng, H., Callender, R., Huang, Z., and Zhang, Z.-Y. (2002). Is PTPase-vanadate a true transition state analog? Biochemistry 41, 5865-5872.
27. Hengge, A. C., Sowa, G., Wu, L., and Zhang, Z.-Y. (1995). Nature of the transition state of the protein-tyrosine phosphatase-catalyzed reaction. Biochemistry 34, 13982-13987.
28. Posner, B. I., Faure, R., Burgess, J. W., Bevan, A. P., Lachance, D., Zhang-Sun, G., Fantus, I. G., Ng, J. B., Hall, D. A., Lum, B. S., and Shaver, A. (1994). Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics. J. Biol. Chem. 269, 4596-4604.
29. Jia, Z., Barford, D., Flint, A. J., and Tonks, N. K. (1995). Structural basis for phosphotyrosine peptide recognition by protein tyrosine phos-phatase 1B. Science 268, 1754-1758.
30. Puius, Y. A., Zhao, Y., Sullivan, M., Lawrence, D. S., Almo, S. C., and Zhang, Z.-Y. (1997). 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.
31. Burke, Jr., T. R., Smyth, M., Nomizu, M., Otaka, A., Roller, P. P.
(1993). Preparation of fluoro- and hydroxy-4-(phosphonomethyl)-d,l-phenylalanine suitable protected for solid-phase synthesis of peptides containing hydrolytically stable analogues of O-phosphotyrosine. J. Org. Chem. 58, 1336-1340.
32. Chen, L., Wu, L., Otaka, A., Smyth, M. S., Roller, P. P., Burke, T. R., den Hertog, J., and Zhang, Z.-Y. (1995) Why is phosphono-difluoromethyl phenylalanine a more potent inhibiting moiety than phosphonomethyl phenylalanine toward protein-tyrosine phos-phatases? Biochem. Biophys. Res. Commun. 216, 976-984.
33. Liotta, A. S., Kole, H. K., Fales, H. M., Roth, J., and Bernier, M. A.
(1994). Synthetic tris-sulfotyrosyl dodecapeptide analogue of the insulin receptor 1146-kinase domain inhibits tyrosine dephosphoryla-tion of the insulin receptor in situ. J. Biol. Chem. 269, 22996-23001.
34. Kole, H. K., Akamatsu, M., Ye, B., Yan, X., Barford, D., Roller, P. P., and Burke, Jr., T. R. (1995). Protein-tyrosine phosphatase inhibition by a peptide containing the phosphotyrosyl mimetic, L-O-malonyltyrosine. Biochem. Biophys. Res. Commun. 209, 817-822.
35. Roller, P. P., Wu, L., Zhang, Z.-Y., and Burke, Jr., T. R. (1998). Potent inhibition of protein-tyrosine phosphatase-1B using the phosphotyro-syl mimetic fluoro-O-malonyl tyrosine (FOMT). Bioorg. Med. Chem. Lett. 8, 2149-2150.
36. Ibrahimi, O. A., Wu, L., Zhao, K., and Zhang, Z.-Y. (2000). Synthesis and characterization of a novel class of protein tyrosine phosphatase inhibitors. Bioorg. Med. Chem. Lett. 10, 457-460.
37. Moran, E. J., Sarshar, S., Cargill, J. F., Shahbaz, M. M., Lio, A., Mjalli, A. M. M., and Armstrong, R. W. (1995). Radio frequency tag encoded combinatorial library method for the discovery of tripeptide-substituted cinnamic acid inhibitors of the protein tyrosine phosphatase PTP1B. J. Am. Chem. Soc. 117, 10787-10788.
38. Burke, Jr., T. R., Yao, Z. J., Zhao, H., Milne, G. W. A., Wu, L., Zhang, Z.-Y., and Voigt, J. H. (1998). Enantioselective synthesis of nonphosphorous-containing phosphotyrosyl mimetics and their use in the preparation of tyrosine phosphatase inhibitory peptides. Tetrahedron 54, 9981-9994.
39. Sarmiento, M., Wu, L., Keng, Y.-F., Song, L., Luo, Z., Huang, Z., Wu, G.-Z., Yuan, A. K., and Zhang, Z.-Y. (2000). Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B. J. Med. Chem. 43, 146-155.
40. Taing, M., Keng, Y.-F., Shen, K., Wu, L., Lawrence, D. S., and Zhang, Z.-Y. (1999). Potent and highly selective inhibitors of the protein tyro-sine phosphatase 1B. Biochemistry 38, 3793-3803.
41. Kotoris, C. C., Chen, M.-J., and Taylor, S. D. (1998). Bioorg. Med. Chem. Lett. 8, 3275-3280.
42. Andersen, H. S., Iversen, L. F., Jeppesen, C. B., Branner, S., Norris, K., Rasmussen, H. B., Moller, K. B., and Moller, N. P. H. (2000). 2-(oxalylamino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases. J. Biol. Chem. 275, 7101-7108.
43. Gao, Y., Voigt, J., Zhao, H., Pais, G. C. G., Zhang, X., Wu, L., Zhang, Z.-Y., and Burke, Jr., T. R., (2001). Utilization of a peptide lead for the discovery of a novel PTP1B-binding motif. J. Med. Chem. 44, 2869-2878.
44. Chen, Y. T., Onaran, M. B., Doss, C. J., and Seto, C. T. (2001). a-Ketocarboxylic acid-based inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. Lett. 11, 1935-1938.
45. Zhang, Z.-Y., Maclean, D., McNamara, D. J., Sawyer, T. K., and Dixon, J. E. (1994). Protein tyrosine phosphatase substrate specificity: the minimum size of the peptide and the positioning of the phosphoty-rosine. Biochemistry 33, 2285-2290.
46. Zhang, Z.-Y., Maclean, D., Thieme-Sefler, A. M., McNamara, D., Dobrusin, E. M., Sawyer, T. K., and Dixon, J. E. (1993). Substrate specificity of the protein tyrosine phosphatases. Proc. Natl. Acad. Sci. USA 90, 4446-4450.
47. Wu, L., Buist, A., den Hertog, J., and Zhang, Z.-Y. (1997). Comparative kinetic analysis and substrate specificity of the tandem catalytic domains of the receptor-like protein- tyrosine phosphatase a. J. Biol. Chem. 272, 6994-7002.
48. Sarmiento, M., Puius, Y. A., Vetter, S. W., Keng, Y.-F., Wu, L., Zhao, Y., Lawrence, D. S., Almo, S. C., and Zhang, Z.-Y. (2000). Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition. Biochemistry 39, 8171-8179.
49. Desmarais, S., Friesen, R. W., Zamboni, R., and Ramachandran, C. (1999). [Difluro(phosphono)methyl]phenylalanine-containing peptide inhibitors of protein tyrosine phosphatases. Biochem. J. 337, 219-223.
50. Jia, Z., Ye, Q., Dinaut, A. N., Wang, Q., Waddleton, D., Payette, P., Ramachandran, C., Kennedy, B., Hum, G., and Taylor, S. D. (2001). Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J. Med. Chem. 44, 4584-4594.
51. Bleasdale, J. E., Ogg, D., Palazuk, B. J., Jacob, C. S., Swanson, M. L., Wang, X. Y., Thompson, D. P., Conradi, R. A., Mathews, W. R., Laborde, A. L., Stuchly, C. W., Heijbel, A., Bergdahl, K., Bannow, C. A., Smith, C. W., Svensson, C., Liljebris, C., Schostarez, H. J., May, P. D., Stevens, F. C., and Larsen, S. D. (2001). Small molecule pep-tidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action. Biochemistry 40, 5642-5654.
52. Liljebris, C., Larsen, S. D., Ogg, D., Palazuk, B. J., and Bleasdale, J. E. (2002). 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.
53. Iversen, L. F., Andersen, H. S., Moller, K. B., Olsen, O. H., Peters, G. H., Branner, S., Mortensen, S. B., Hansen, T. K., Lau, J., Ge, Y., Holsworth, D. D., Newman, M. J., and Moller N. P. H. (2001). Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases. Biochemistry 40, 14812-14820.
54. Shen, K., Keng, Y.-F., Wu, L., Guo, X.-L., Lawrence, D. S., and Zhang, Z.-Y. (2001). Acquisition of a specific and potent PTP1B
inhibitor from a novel combinatorial library and screening procedure. J. Biol. Chem. 276, 47311-47319.
55. Burke, Jr., T. R. and Zhang, Z.-Y. (1998). Protein tyrosine phosphatases: structure, mechanism and inhibitor discovery. Biopolymers (Peptide Sci.) 47, 225-241.
56. Ripka, W. C. (2000). Protein tyrosine phosphatase inhibition. Annu. Rep. Med. Chem. 35, 231-250.
57. Zhang, Z.-Y. (2002). Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. Annu. Rev. Pharmacol. Toxicol. 42, 209-234.
58. Lazo, J. S., Nemoto, K., Pestell, K. E., Cooley, K., Southwick, E. C., Mitchell, D. A., Furey, W., Gussio, R., Zaharevitz, D. W., Joo, B., and Wipf, P. (2002). Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors. Mol. Pharmacol. 61, 720-728.
59. Urbanek, R. A., Suchard, S. J., Steelman, G. B., Knappenberger, K. S., Sygowski, L. A., Veale, C. A., and Chapdelaine, M. J. (2001). Potent reversible inhibitors of the protein tyrosine phosphatase CD45. J. Med. Chem. 44, 1777-1793.
60. Zhang, Y.-L., Keng, Y.-F., Zhao, Y., Wu, L., and Zhang, Z.-Y. (1998). Suramin is an active site-directed, reversible, and tight-binding inhibitor of protein-tyrosine phosphatases. J. Biol. Chem. 273, 12281-12287.
61. Pathak, M. K. and Yi, T. (2001). Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J. Immunol. 167, 3391-3397.
62. Guo, X.-L., Sher, K., Wang, F., Lawrence, D. S., and Zhang, Z.-Y. (2002). Probing the molecular basis for potent and selective protein tyrosine phosphatase 1B inhibition. J. Biol. Chem. 277, 41014-41022.
Was this article helpful?