Bringing It All Together: Future Challenges
During the last few years there has been significant progress in the development of PTP inhibitors. Using structure-based design approaches, several groups have shown that it is possible to synthesize highly potent and selective non-phosphorus, non-peptide inhibitors of PTP1B. However, at this point these achievements seem to have been reached at the expense of appropriate pharmacokinetic properties, including cellular uptake. Therefore, the next wave within the field of PTP inhibitors is likely to be focused on improvements in this respect.
Furthermore, although very significant progress has been achieved with respect to design of selective PTP1B inhibitors (see Sect. 9), it remains to be demonstrated that drug-like PTP1B inhibitors can be made that do not recognize TC-PTP. TC-PTP is the closest homolog to PTP1B, sharing about 74 percent identity at the amino acid level in the catalytic domains. TC-PTP exists both as a 48-kDa endoplasmic reticulum-targeted form (TC48) and a 45-kDa nuclear form (TC45). Since both PTP1B and TC48 are bound to the endoplasmic reticulum via their C-terminal extensions, it might be speculated that these two PTPs serve similar, perhaps even overlapping, functions. Indeed, in a recent publication it was suggested that TC-PTP is involved in the regulation of insulin signaling (Galic et al. 2003). However, it should be noted that TC-PTP knockout mice, in contrast to PTP1B knockout mice (Elchebly et al. 1999; Klaman et al. 2000), die a few weeks after birth, whereas heterozygous mice seem to have normal lifespan (Ibarra-Sanchez et al. 2000). At present, it is therefore unclear if PTP1B inhibitors that also recognize TC-PTP will be beneficial or harmful. To provide the structural framework for design of inhibitors that are selective for either PTP1B or TC-PTP, we have recently reported the X-ray structure of apo TC-PTP (Iversen et al. 2002). Of note, and as indicated above, two groups have provided structure-based evidence that inhibitors that are selective for PTP1B over TC-PTP are within reach (see Sect. 9.3).
Another challenge facing the PTP field is the fact that PTPs themselves seem to be regulated by covalent modifications, e.g., phosphorylation. In particular, modifications close to the active site may influence not only sub strate, but also inhibitor binding. As an example, recent studies indicate that the activity of PTP1B may be influenced by phosphorylation of Ser50 (Ravichandran et al. 2001), which is positioned close to the selectivity-determining region defined by residues 47-48 and 258-259. It is quite likely that the position of the side chains of these residues will be influenced by a bulky, charged phosphate group on Ser50. Since all structure-based design activities up to this point have been carried out with catalytic domains produced in E. coli, it is suggested that future design efforts include testing of lead compounds either in appropriately covalently modified recombinant enzymes or in a relevant cellular context. It should also be mentioned that the activity of PTPs may be greatly influenced by domains outside the catalytic domains, and again this has to be taken into account in future PTP inhibitor development programs.
As has become apparent, almost all activities so far have been directed towards development of selective PTP1B inhibitors. However, several other classical PTPs and dual-specificity PTPs may be important novel drug targets, indicating that the focus on general PTP inhibitors may be a powerful platform for the discovery of novel therapeutics. Consistent with this concept, we have been able to use the original scaffold, OBA, as a template for synthesis of highly potent inhibitors of PTPb with significant selectivity over PTP1B, and pharmacological characterization of such compounds may reveal new biological insights and potential clinical applications (Lund et al. 2004).
Finally, it should be, emphasized that the discovery of the transient formation of sulphenyl-amide as described in Sect. 6 may represent an exiting new avenue for structure-based design of PTP inhibitors. The significant conformational changes imposed by the sulphenyl-amide in the active site prevent binding of pTyr substrates and probably all currently known active site-dependent inhibitors. The formation of the sulphenyl-amide is reversible, and it is believed to occur in vivo after stimulation of receptor-tyrosine kinases, resulting in H2O2 formation. Therefore, compounds that bind to the sulphenyl-amide form of PTPs, and not to the wild-type enzymes, are expected to inhibit already-activated signaling pathways only, thereby possibly providing an additional level of specificity and limiting the risk of side effects.
Acknowledgements The authors thank (1) James G. McCormack, OSI Pharmaceuticals, Karin Bach M0ller, Novo Nordisk, and Jannik N. Andersen (J.N.A.), Cold Spring Harbor Laboratory, for helpful discussions and critical reading of the manuscript; (2) J.N.A. for graphical assistance, and (3) Michael Jirousek, Gang Liu, and Cele Abad-Zapatero for sharing the coordinates of 1Q1 M with us prior to PDB release.
Ahmad F, Considine RV, Goldstein BJ (1995) Increased abundance of receptor-type pro-tein-tyrosine phosphatase LAR accounts for the elevated insulin receptor dephos-phorylating activity in adipose tissue of obese human subjects. J Clin Invest 95:2806-2812
Akamatsu M, Roller PP, Chen L, Zhang ZY, Ye B, Burke TR (1997) Potent inhibition of protein-tyrosine phosphatase by phosphotyrosine-mimic containing cyclic peptides. Bioorg Med Chem 5:157-163 Amoui M, Baylink DJ, Tillman JB, Lau K-HW (2003) Expression of a structurally unique osteoclastic protein-tyrosine phosphatase is driven by an alternative intronic, cell-type-specific promoter. J Biol Chem M303933200 Andersen HS, Iversen LF, Jeppesen CB, Branner S, Norris K, M0ller KB, M0ller NPH (2000) 2-(Oxalyl-amino)-benzoic acid is a general, competitive inhibitor of protein-tyrosine phosphatases. J Biol Chem 275:7101-7108 Andersen HS, Olsen OH, Iversen LF, Sorensen ALP, Mortensen SB, Christensen MS, Branner S, Hansen TK, Lau JF, Jeppesen L, Moran EJ, Su J, Bakir F, Judge L, Shahbaz M, Collins T, Vo T, Newman MJ, Ripka WC, M0ller NPH (2002) Discovery and SAR of a novel selective and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B. J Med Chem 45:4443-4459 Andersen JN, Mortensen OH, Peters GH, Drake PG, Iversen LF, Olsen OH, Jansen PG, Andersen HS, Tonks NK, M0ller NPH (2001) Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol 21:7117-7136 Asante-Appiah E, Ball K, Bateman K, Skorey K, Friesen R, Desponts C, Payette P, Bayly C, Zamboni R, Scapin G, Ramachandran C, Kennedy BP (2001) The YRD motif is a major determinant of substrate and inhibitor specificity in T-cell protein-tyrosine phos-phatase. J Biol Chem 276:26036-26043 Asante-Appiah E, Patel S, Dufresne C, Roy P, Wang QP, Patel V, Friesen RW, Ramachandran C, Becker JW, Leblanc Y, Kennedy BP, Scapin G (2002) The structure of PTP-1B in complex with a peptide inhibitor reveals an alternative binding mode for bisphosphonates. Biochemistry 41:9043-9051 Barford D, Flint AJ, Tonks NK (1994) Crystal-structure of human protein-tyrosine-phos-
phatase 1B. Science 263:1397-1404 Bilwes AM, Den Hertog J, Hunter T, Noel JP (1996) Structural basis for inhibition of receptor protein-tyrosine phosphatase-alpha by dimerization. Nature 382:555-559 Blanchetot C, Den Hertog J (2000) Antibody-induced dimerization of HARPTPalpha-EGFR chimera suggests a ligand dependent mechanism of regulation for RPTP alpha. FEBS Lett 484:235-240 Blanchetot C, Tertoolen LG, Overvoorde J, Den Hertog J (2002a) Intra- and intermolecular interactions between intracellular domains of receptor protein-tyrosine phospha-tases. J Biol Chem 277:47263-47269 Blanchetot C, Tertoolen LGJ, Den Hertog J (2002b) Regulation of receptor protein-tyro-
sine phosphatase alpha by oxidative stress. EMBO J 21:493-503 Blaskovich MA, Kim HO (2002) Recent discovery and development of protein tyrosine phosphatase inhibitors. Expert Opin Ther Patents 12:871-905 Bleasdale JE, Ogg D, Palazuk BJ, Jacob CS, Swanson ML, Wang XY, Thompson DP, Conradi RA, Mathews WR, Laborde AL, Stuchly CW, Heijbel A, Bergdahl K, Bannow CA, Smith CW, Svensson C, Liljebris C, Schostarez HJ, May PD, Stevens FC, Larsen SD (2001) Small molecule peptidomimetics containing a novel phosphotyrosine bioisostere inhibit protein tyrosine phosphatase 1B and augment insulin action. Biochemistry 40:5642-5654 Burke TR Jr, Zhang Z-Y (1998) Protein-tyrosine phosphatases: structure, mechanism, and inhibitor discovery. Biopolymers 47:225-241 Burke TR, Lee K (2003) Phosphotyrosyl mimetics in the development of signal transduction inhibitors. Acc Chem Res 36:426-433 Burke TR, Kole HK, Roller PP (1994) Potent inhibition of insulin-receptor dephosphory-lation by a hexamer peptide-containing the phosphotyrosyl mimetic F2Pmp. Bio-chem Biophys Res Commun 204:129-134 Burke TR, Ye B, Akamatsu M, Ford H, Yan XJ, Kole HK, Wolf G, Shoelson SE, Roller PP (1996a) 4'-O-[2-(2-fluoromalonyl)]-l-tyrosine—a phosphotyrosyl mimic for the preparation of signal-transduction inhibitory peptides. J Med Chem 39:1021-1027 Burke TR, Ye B, Yan XJ, Wang SM, Jia ZC, Chen L, Zhang ZY, Barford D (1996b) Small-molecule interactions with protein-tyrosine-phosphatase ptp1b and their use in inhibitor design. Biochemistry 35:15989-15996 Burke TR Jr, Yao Z-J, Zhao H, Milne GWA, Wu L, Zhang Z-Y, Voigt JH (1998) Enantiose-lective synthesis of nonphosphorous-containing phosphotyrosyl mimetics and their use in the preparation of tyrosine phosphatase inhibitory peptides. Tetrahedron 54:9981-9994
Calera MR, Vallega G, Pilch PF (2000) Dynamics of protein-tyrosine phosphatases in rat adipocytes. J Biol Chem 275:6308-6312 Charbonneau H, Tonks NK (1992) 1002 Protein phosphatases. Annu Rev Cell Biol 8:463493
Chen L, Wu L, Otaka A, Smyth MS, Roller PP, Burke TR, Denhertog J, Zhang ZY (1995) Why is phosphonodifluoromethyl phenylalanine a more potent inhibitory moiety than phosphonomethyl phenylalanine toward protein-tyrosine phosphatases. Bio-chem Biophys Res Commun 216:976-984 Cheng A, Uetani N, Simoncic PD, Chaubey VP, Lee-Loy A, Mcglade CJ, Kennedy BP, Tremblay ML (2002) Attenuation of leptin action and regulation of obesity by protein tyrosine phosphatase 1B. Dev Cell 2:497-503 Cho HJ, KrishnarajR, Itoh M, Kitas E, Bannwarth W, Saito H, Walsh CT (1993) Substrate specificities of catalytic fragments of protein-tyrosine phosphatases (hPTP-b, LAR, and CD45) toward phosphotyrosylpeptide substrates and thiophosphotyrosylated peptides as inhibitors. Protein Sci 2:977-984 Clemens JC, Guan K, Bliska JB, Falkow S, Dixon JE (1991) Microbial pathogenesis and tyrosine dephosphorylation: surprising 'bedfellows'. Mol Microbiol 5:2617-2620 Cohen P (2002) Protein kinases—the major drug targets of the twenty-first century? Nat
Rev Drug Discov 1:309-315 Cong LN, Chen H, Li YH, Lin CH, Sap J, Quon MJ (1999) Overexpression of protein tyrosine phosphatase-alpha (PTP- alpha) but not PTP-kappa inhibits translocation of GLUT4 in rat adipose cells. Biochem Biophys Res Commun 255:200-207 Czech MP, Lawrence JC, Lynn WS (1974a) Evidence for electron transfer reactions involved in the Cu2+ -dependent thiol activation of fat cell glucose utilization. J Biol Chem 249:1001-1006
Czech MP, Lawrence JC, Lynn WS (1974b) Evidence for the involvement of sulfhydryl oxidation in the regulation of fat cell hexose transport by insulin. Proc Natl Acad Sci USA 71:4173-4177
Czech MP, Lawrence JC, Lynn WS (1974c) Hexose transport in isolated brown fat cells. A model system for investigating insulin action on membrane transport. J Biol Chem 249:5421-5427
Denu JM, Dixon JE (1998) Protein tyrosine phosphatases: Mechanisms of catalysis and regulation. Curr Opin Chem Biol 2:633-641 Denu JM, Tanner KG (1998) Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37:5633-5642 Denu JM, Lohse DL, Vijayalakshmi J, Saper MA, Dixon JE (1996) Visualization of intermediate and transition-state structures in protein-tyrosine-phosphatase catalysis. Proc Natl Acad Sci USA 93:2493-2498 Desmarais S, Jia Z, Ramachandaran C (1998) Inhibition of protein tyrosine phosphatase
PTP1B and CD45 by sulfotyrosyl peptides. Arch Biochem Biophys 354:225-231 Desmarais S, Friesen RW, Zamboni R, Ramachandaran C (1999) [Difluro(phospho-no)methyl]phenyl-containing peptide inhibitors of protein tyrosine phosphatases. Biochem J 337:219-223 Domchek SM, Auger KR, Chatterjee S, Burke TRJ, Shoelson SE (1992) Inhibition of SH2 domain-phosphoprotein association by a nonhydrolyzable phosphonopeptide. Biochemistry 31:9865-9870 Dubyak GR, Kleinzeller A (1980) The insulin-mimetic effects of vanadate in isolated rat adipocytes. Dissociation from effects of vanadate as a (Na+-K+)ATPase inhibitor. J Biol Chem 255:5306-5312 Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S, Loy AL, Normandin D, Cheng A, Himms-Hagen J, Chan C-C, Ramachandaran C, Gresser MJ, Tremblay ML, Kennedy BP (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544-1548 Elson A, Leder P (1995) Identification of a cytoplasmic, phorbol ester-inducible isoform of protein-tyrosine-phosphatase epsilon. Proc Natl Acad Sci USA 92:12235-12239 Erlanson DA, McDowell RS, He MM, Randal M, Simmons RL, Kung J, Waight A, Hansen SK (2003) Discovery of a new phosphotyrosine mimetic for PTP1B using breakaway tethering. J Am Chem Soc 125:5602-5603 Fantus IG, Kadota S, Deragon G, Foster B, Posner BI (1989) Pervanadate [peroxide(s) of vanadate] mimics insulin action in rat adipocytes via activation of the insulin receptor tyrosine kinase. Biochemistry 28:8864-8871 Fauman EB, Yuvaniyama C, Schubert HL, Stuckey JA, Saper MA (1996) The x-ray crystal-structures of yersinia tyrosine phosphatase with bound tungstate and nitrate— mechanistic implications. J Biol Chem 271:18780-18788 Fischer EH, Charbonneau H, Tonks NK (1991) Protein tyrosine phosphatases: a diverse family of intracellular and transmembrane enzymes. Science 253:401-406 Flint AJ, Gebbink MFGB, Franza BR, Hill DE, Tonks NK (1993) Multisite phosphorylation of the protein-tyrosine phosphatase, PTB1B—identification of cell-cycle regulated and phorbol ester stimulated sites of phosphorylation. EMBO J 12:1937-1946 Flint AJ, Tiganis T, Barford D, Tonks NK (1997) Development of substrate-trapping mutants to identify physiological substrates of protein-tyrosine phosphatases. Proc Natl Acad Sci USA 94:1680-1685 Frangione JV, Oda A, Smith M, Salzman EW, Neel BG (1993) Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets. EMBO J 12:4843-4856 Fukada T, Tonks NK (2003) Identification of YB-1 as a regulator of PTP1B expression:
implications for regulation of insulin and cytokine signaling. EMBO J 22:479-493 Galic S, Klingler-Hoffmann M, Fodero-Tavoletti MT, Puryer MA, Meng TC, Tonks NK, Tiganis T (2003) Regulation of insulin receptor signaling by the protein tyrosine phosphatase TCPTP. Mol Cell Biol 23:2096-2108
Gil-Henn H, Volohonsky G, Toledano-Katchalski H, Gandre S, Elson A (2000) Generation of novel cytoplasmic forms of protein tyrosine phosphatase epsilon by proteolytic processing and translational control. Oncogene 19:4375-4384 Gil-Henn H, Volohonsky G, Elson A (2001) Regulation of protein-tyrosine phosphatases alpha and epsilon by calpain-mediated proteolytic cleavage. J Biol Chem 276:3177231779
Glaser F, Pupko T, Paz I, Bell RE, Bechor-Shental D, Martz E, Ben Tal N (2003) ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics 19:163-164 Glover NR, Tracey AS (2000) The phosphatase domains of LAR, CD45, and PTP1B: structural correlations with peptide-based inhibitors. Biochem Cell Biol 78:39-50 Gross S, Knebel A, Tenev T, Neininger A, Gaestel M, Herrlich P, Bohmer FD (1999) Inac-tivation of protein-tyrosine phosphatases as mechanism of UV-induced signal trans-duction. J Biol Chem 274:26378-26386 Groves MR, Yao Z-J, Roller PP, Burke TR, Barford D (1998) Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics. Biochemistry 37:17773-17783 Guan KL, Dixon JE (1990) Protein tyrosine phosphatase activity of an essential virulence determinant in Yersinia. Science 249:553-556 Guan KL, Dixon JE (1991) Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. J Biol Chem 266:17026-17030 Hatakeyama M (2003) Helicobacter pylori CagA-a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes Infect 5:143-150
Heffetz D, Zick Y (1992) The insulinomimetic agents hydrogen peroxide and vanadate stimulate tyrosine phosphorylation of potential target proteins for the insulin- receptor kinase in intact-cells. Biochem J 288:631-635 Heffetz D, Bushkin I, Dror R, Zick Y (1990) The insulinomimetic agents H2O2 and vana-date stimulate protein tyrosine phosphorylation in intact cells. J Biol Chem 265:2896-2902
Hermiston ML, Xu Z, Weiss A (2003) CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol 21:107-137 Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M (2002) SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295:683-686 Hoppe E, Berne PF, Stock D, Rasmussen JS, M0ller NPH, Ullrich A, Huber R (1994) Expression, purification and crystallization of human phosphotyrosine phosphatase 1B. Eur J Biochem 223:1069-1077 Ibarra-Sanchez MD, Simoncic PD, Nestel FR, Duplay P, Lapp WS, Tremblay ML (2000)
The T-cell protein tyrosine phosphatase. Semin Immunol 12:379-386 Irie-Sasaki J, Sasaki T, Penninger JM (2003) CD45 regulated signaling pathways. Curr Top Med Chem 3:783-796
Iversen LF, Andersen HS, Branner S, Mortensen SB, Peters GH, Norris K, Olsen OH, Jeppesen CB, Lundt BF, Ripka W, M0ller KB, M0ller NPH (2000) Structure-based design of a low molecular weight, nonphosphorus, nonpeptide, and highly selective inhibitor of protein-tyrosine phosphatase 1B. J Biol Chem 275:10300-10307 Iversen LF, Andersen HS, M0ller KB, Olsen OH, Peters GH, Branner S, Mortensen SB, Hansen TK, Lau J, Ge Y, Holsworth DD, Newman MJ, M0ller NPH (2001) Steric hindrance as basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases. Biochemistry 40:14812-14820
Iversen LF, M0ller KB, Pedersen AK, Peters GH, Petersen AS, Andersen HS, Branner S, Mortensen SB, M0ller NP (2002) Structure determination of T cell protein tyrosine phosphatase. J Biol Chem 277:19982-19990 Jackson DE (2003) The unfolding tale of PECAM-1. FEBS Lett 540:7-14 Jia Z, Ye Q, Dinaut AN, Wang Q, Waddleton D, Payette P, Ramachandran C, Kennedy B, Hum G, Taylor SD (2001) Structure of protein tyrosine phosphatase 1B in complex with inhibitors bearing two phosphotyrosine mimetics. J Med Chem 44:4584-4594 Jia ZC, Barford D, Flint AJ, Tonks NK (1995) Structural basis for phosphotyrosine peptide recognition by protein-tyrosine-phosphatase 1b. Science 268:1754-1758 Jiang GL, Den Hertog J, Su J, Noel J, Sap J, Hunter T (1999) Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-alpha. Nature 401:606-610 Jiang GQ, Den Hertog J, Hunter T (2000) Receptor-like protein tyrosine phosphatase alpha homodimerizes on the cell surface. Mol Cell Biol 20:5917-5929 Johnson TO, Ermolieff J, Jirousek MR (2002) Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov 1:696-709 Kadota S, Fantus IG, Deragon G, Guyda HJ, Hersh B, Posner BI (1987) Peroxide(s) of Vanadium: a novel and potent insulin-mimetic agent which activates the insulin receptor kinase. Biochem Biophys Res Commun 14:259-266 Kaniga K, Uralil J, Bliska JB, Galan JE (1996) A secreted protein-tyrosine-phosphatase with modular effector domains in the bacterial pathogen salmonella-typhimurium. Mol Microbiol 21:633-641 Kar S, Wang MF, Wilcox CS, Carr BI (2003) Antitumor and anticarcinogenic actions of
Cpd 5: a new class of protein phosphatase inhibitor. Carcinogenesis 24:411-416 Kennedy BP (1999) Role of protein tyrosine phosphatase-1B in diabetes and obesity.
Biomed Pharmacother 53:466-470 Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, Moghal N, Lubkin M, Kim YB, Sharpe AH, Stricker-Krongrad A, Shulman GI, Neel BG, Kahn BB (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20:5479-5489 Kole HK, Akamatsu M, Ye B, Yan XJ, Barford D, Roller PP, Burke TR (1995a) Protein-ty-rosine-phosphatase inhibition by a peptide-containing the phosphotyrosyl mimetic, L-O-malonyltyrosine. Biochem Biophys Res Commun 209:817-822 Kole HK, Smyth MS, Russ PL, Burke TR (1995b) Phosphonate inhibitors of protein-tyro-
sine and serine threonine phosphatases. Biochem J 311:1025-1031 Kole HK, Garant MJ, Kole S, Bernier M (1996) A peptide-based protein-tyrosine-phos-phatase inhibitor specifically enhances insulin-receptor function in intact cells. J Biol Chem 271:14302-14307 Koshio O, Akanuma Y, Kasuga M (1988) Hydrogen peroxide stimulates tyrosine phos-phorylation of the insulin receptor and its tyrosine kinase activity in intact cells. Biochem J 250:95-101
Kotoris CC, Chen M, Taylor SD (1998) Novel phosphate mimetics for the design of non-peptidyl inhibitors of protein tyrosine phosphatases. Bioorg Med Chem Lett 8:32753280
Koul A, Choidas A, Treder M, Tyagi AK, Drlica K, Singh Y, Ullrich A (2000) Cloning and characterization of secretory tyrosine phosphatases of Mycobacterium tuberculosis. J Bacteriol 182:5425-5432 Kulas DT, Zhang W-R, Goldstein BJ, Furlanetto RW, Mooney RA (1995) Insulin receptor signaling is augmented by antisense inhibition of the protein tyrosine phosphatase LAR. J Biol Chem 270:2435-2438
Larsen SD, Stevens FC, Lindberg TJ, Bodnar PM, O'Sullivan TJ, Schostarez HJ, Palazuk BJ, Bleasdale JE (2003) Modification of the N-terminus of peptidomimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors: Identification of analogues with cellular activity. Bioorg Med Chem Lett 13:971-975 Lee K, Burke TR (2003) CD45 protein-tyrosine phosphatase inhibitor development. Curr
Top Med Chem 3:797-807 Liotta AS, Kole HK, Fales HM, Roth J, Bernier M (1994) A synthetic tris-sulfotyrosyl do-decapeptide analog of the insulin-receptor 1146-kinase domain inhibits tyrosine de-phosphorylation of the insulin-receptor in-situ. J Biol Chem 269:22996-23001 Liu G, Szczepankiewicz BG, Pei ZH, Janowick DA, Xin ZL, Hajduk PJ, Abad-Zapatero C, Liang H, Hutchins CW, Fesik SW, Ballaron SJ, Stashko MA, Lubben T, Mika AK, Zinker BA, Trevillyan JM, Jirousek MR (2003a) Discovery and structure-activity relationship of oxalylarylaminobenzoic acids as inhibitors of protein tyrosine phosphatase 1B. J Med Chem 46:2093-2103 Liu G, Xin Z, Pei Z, Hajduk PJ, Abad-Zapatero C, Hutchins CW, Zhao H, Lubben TH, Ballaron SJ, Haasch DL, Kaszubska W, Rondinone CM, Trevillyan JM, Jirousek MR (2003b) Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J Med Chem 46:4232-4235 Liu G, Xin ZL, Liang H, Abad-Zapatero C, Hajduk PJ, Janowick DA, Szczepankiewicz BG, Pei z, Hutchins CW, Ballaron SJ, Stashko MA, Lubben TH, Berg CE, Rondinone CM, Trevillyan JM, Jirousek MR (2003c) Selective protein tyrosine phosphatase 1B inhibitors: targeting the second phosphotyrosine binding site with non-carboxylic acid-containing ligands. J Med Chem 46:3437-3440 Lohse DL, Denu JM, Santoro N, Dixon JE (1997) Roles of aspartic acid-181 and serine-222 in intermediate formation and hydrolysis of the mammalian protein-tyrosine-phosphatase PTP1. Biochemistry 36:4568-4575 Lund IK, Andersen HS, Iversen LF, Olsen OH, Moller KB, Pedersen AK, Ge Y, Holsworth DD, Newman MJ, Axe FU, and Moller NPH (2004) Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase beta. J Biol Chem 279:24226-24235
Maehama T, Taylor GS, Dixon JE (2001) PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 70:247-279 Mahadev K, Wu XD, Zilbering A, Zhu L, Lawrence JTR, Goldstein BJ (2001a) 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 Mahadev K, Zilbering A, Zhu L, Goldstein BJ (2001b) Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1B in vivo and enhances the early insulin action cascade. J Biol Chem 276:21938-21942 Majeti R, Bilwes AM, Noel JP, Hunter T, Weiss A (1998) Dimerization-induced inhibition of receptor protein-tyrosine- phosphatase function through an inhibitory wedge. Science 279:88-91
Majeti R, Xu Z, Parslow TG, Olson JL, Daikh DI, Killeen N, Weiss A (2000) An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103:1059-1070 Mauro LJ, Dixon JE (1994) 'Zip codes' direct intracellular protein tyrosine phosphatases to the correct cellular 'address'. TIBS 19:151-155 May JM, de Haen C (1979) Insulin-stimulated intracellular hydrogen peroxide production in rat epididymal fat cells. J Biol Chem 254:2214-2220 McGovern SL, Shoichet BK (2003) Kinase inhibitors: not just for kinases anymore. J Med Chem 46:1478-1483
McGovern SL, Caselli E, Grigorieff N, Shoichet BK (2002) A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem 45:1712-1722
Meng TC, Fukada T, Tonks NK (2002) Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol Cell 9:387-399 Milarski KL, Zhu G, Pearl CG, McNamara DJ, Dobrusin EM, MacLean D, Thieme-Sefler A, Zhang Z-Y, Sawyer T, Decker SJ, Dixon JE, Saltiel AR (1993) Sequence specificity in recognition of the epidermal growth factor receptor by protein tyrosine phosphatase 1B. J Biol Chem 268:23634-23639 Miller MJ, Bracccolino DS, Cleary DG, Ream JE, Walker MC, Sikorski JA (1994) EPSP synthase inhibitor design IV. New aromatic substrate analogs and symmetrical inhibitors containing novel 3-phosphate mimics. Bioorg Med Chem Lett 4:2605-2608 Moeslein FM, Myers MP, Landreth GE (1999) The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. J Biol Chem 274:26697-26704
M0ller NPH, M0ller KB, Lammers R, Kharitonenkov A, Sures I, Ullrich A (1994a) Src ki-nase associates with a member of a distinct subfamily of protein-tyrosine phospha-tases containing an ezrin-like domain. Proc Natl Acad Sci U S A 91:7477-7481 M0ller NPH, M0ller KB, Ullrich A, M0ller NP (1994b) New protein tyrosine phosphatase PTP-S31 is used to develop products for treating or preventing disease associated with abnormal PTP-531, e.g., cancer or diabetes. Max Planck Ges Foerderung Wissenschaften, [W09421800-A2], pp 9-29 M0ller NPH, M0ller KB, Lammers R, Kharitonenkov A, Hoppe E, Wiberg FC, Sures I, Ullrich A (1995) Selective down-regulation of the insulin receptor signal by protein-tyrosine phosphatases alpha and epsilon. J Biol Chem 270:23126-23131 M0ller NPH, Iversen LF, Andersen HS, McCormack JG (2000) Protein tyrosine phosphatases (PTPs) as drug targets: inhibitors of PTP-1B for the treatment of diabetes. Curr Opin Drug Discov Devel 3:527-540 Mooney RA, LeVea CM (2003) The leukocyte common antigen-related protein LAR: candidate PTP for inhibitory targeting. Curr Top Med Chem 3:809-819 Murli S, Watson RO, Galan JE (2001) Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells. Cell Microbiol 3:795-810 Myers MP, Andersen JN, Cheng A, Tremblay ML, Horvath CM, Parisien JP, Salmeen A, Barford D, Tonks NK (2001) TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem 276:47771-47774 Norris K, Norris F, Kono DH, Vestergaard H, Pedersen O, Theofilopoulos AN, M0ller NPH (1997) Expression of protein-tyrosine phosphatases in the major insulin target tissues. FEBS Lett 415:243-248 Pallen CJ (2003) Protein tyrosine phosphatase alpha (PTPalpha): a Src family kinase activator and mediator of multiple biological effects. Curr Top Med Chem 3:821-835 Pannifer ADB, Flint AJ, Tonks NK, Barford D (1998) Visualization of the cysteinyl-phos-phate intermediate of a protein-tyrosine phosphatase by X-ray crystallography. J Biol Chem 273:10454-10462 Patankar SJ, Jurs PC (2003) Classification of inhibitors of protein tyrosine phosphatase
1B using molecular structure based descriptors. J Chem Inf Comput Sci 43:885-899 Pathak MK, Yi TL (2001) Sodium stibogluconate is a potent inhibitor of protein tyrosine phosphatases and augments cytokine responses in hemopoietic cell lines. J Immunol 167:3391-3397
Pathak MK, Dhawan D, Lindner DJ, Borden EC, Farver C, Yi TL (2002) Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Mol Cancer Ther 1:12551264
Peters GH, Iversen LF, Branner S, Andersen HS, Mortensen SB, Olsen OH, M0ller KB, M0ller NPH (2000) Residue 259 is a key determinant of substrate specificity of pro-tein-tyrosine phosphatases 1B and a. J Biol Chem 275:18201-18209 Pot DA, Dixon JE (1992a) A thousand and two protein tyrosine phosphatases. Biochim
Biophys Acta 1136:35-43 Pot DA, Dixon JE (1992b) Active site labeling of a receptor-like protein tyrosine phosphatase. J Biol Chem 267:140-143 Puius YA, Zhao Y, Sullivan M, Lawrence DS, Almo SC, 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 Ragab A, Bodin S, Viala C, Chap H, Payrastre B, Ragab-Thomas J (2003) The tyrosine phosphatase 1B regulates LAT phosphorylation and platelet aggregation upon Fcgamma RIIa cross-linking. J Biol Chem 278:40923-40932 Ramachandran C, Kennedy BP (2003) Protein tyrosine phosphatase 1B: a novel target for type 2 diabetes and obesity. Curr Top Med Chem 3:749-757 Ravichandran LV, Chen H, Li YH, Quon MJ (2001) Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor. Mol Endocrinol 15:1768-1780
Ripka WC (2000) Protein tyrosine phosphatase inhibition. Annu Rep Med Chem 35:231250
Ruzzene M, Donella DA, Marin O, Perich JW, Ruzza P, Borin G, Calderan A, Pinna LA (1993) Specificity of T-cell protein tyrosine phosphatase toward phosphorylated synthetic peptides. Eur J Biochem 211:289-295 Salmeen A, Andersen JN, Myers MP, Tonks NK, Barford D (2000) Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyro-sine phosphatase 1B. Mol Cell 6:1401-1412 Salmeen A, Andersen JN, Myers MP, Meng TC, Hinks JA, Tonks NK, Barford D (2003) Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423:769-773 Sarmiento M, Zhao Y, Gordon SJ, Zhang Z-Y (1998) Molecular-basis for substrate-specificity of protein-tyrosine-phosphatase 1B. J Biol Chem 273:26368-26374 Sarmiento M, Puius YA, Vetter SW, Keng YF, Wu L, Zhang Z-Y (2000) Structural basis of plasticity in protein tyrosine phosphatase 1B substrate recognition. Biochemistry 39:8171-8179
Scapin G, Patel S, Patel V, Kennedy B, Asante-Appiah E (2001) The structure of apo pro-tein-tyrosine phosphatase 1B C215S mutant: more than just an S^O change. Protein Sci 10:1596-1605
Schubert HL, Fauman EB, Stuckey JA, Dixon JE, Saper MA (1995) A ligand-induced con-formational change in the yersinia protein-tyrosine-phosphatase. Protein Sci 4:1904-1913
Shen K, Keng YF, Wu L, Guo XL, Lawrence DS, Zhang ZY (2001) Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. J Biol Chem 276:47311-47319 Shifrin VI, Neel BG (1993) Growth factor-inducible alternative splicing of nontransmem-brane phosphotyrosine phosphatase PTP-1B premessenger rna. J Biol Chem 268:25376-25384
Skorey K, Ly HD, Kelly J, Hammond M, Ramachandran C, Huang Z, Gresser MJ, Wang QP (1997) How does alendronate inhibit protein-tyrosine phosphatases. J Biol Chem 272:22472-22480
Skorey KI, Kennedy BP, Friesen RW, Ramachandran C (2001) Development of a robust scintillation proximity assay for protein tyrosine phosphatase 1B using the catalyti-cally inactive (C215S) mutant. Anal Biochem 291:269-278 Smyth MS, Ford H, Jr, Burke TR Jr (1992) A general-method for the preparation of ben-zylic alpha,alpha-difluorophosphonic acids—nonhydrolyzable mimetics of phospho-tyrosine. Tetrahedron Lett 33:4137-4140 Stuckey JA, Schubert HL, Fauman EB, Zhang ZY, Dixon JE, Saper MA (1994) Crystal-structure of yersinia protein-tyrosine-phosphatase at 2. 5-angstrom and the complex with tungstate. Nature 370:571-575 Sun JP, Fedorov AA, Lee SY, Guo XL, Shen K, Lawrence DS, Almo SC, Zhang ZY (2003) Crystal structure of PTP1B complexed with a potent and selective bidentate inhibitor. J Biol Chem 278:12406-12414 Szczepankiewicz BG, Liu G, Hajduk PJ, Abad-Zapatero C, Pei ZH, Xin ZL, Lubben TH, Trevillyan JM, Stashko MA, Ballaron SJ, Liang H, Huang F, Hutchins CW, Fesik SW, Jirousek MR (2003) Discovery of a potent, selective protein tyrosine phosphatase 1B inhibitor using a linked-fragment strategy. J Am Chem Soc 125:4087-4096 Taing M, Keng YF, Shen K, Wu L, Lawrence DS, Zhang ZY (1999) Potent and highly selective inhibitors of the protein tyrosine phosphatase 1B. Biochemistry 38:3793-3803 Tamura S, Brown TA, Whipple JH, Fujita-Yamaguchi Y, Dubler RE, Cheng K, Larner J (1984) A novel mechanism for the insulin-like effect of vanadate on glycogen synthase in rat adipocytes. J Biol Chem 259:6650-6658 Tanuma N, Nakamura K, Kikuchi K (1999) Distinct promoters control transmembrane and cytosolic protein tyrosine phosphatase epsilon expression during macrophage differentiation. Eur J Biochem 259:46-54 Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34:148-150
Taylor SD, Kotoris CC, Dinaut AN, Wang QP, Ramachandran C, Huang Z (1998) Potent non-peptidyl inhibitors of protein-tyrosine- phosphatase 1b. Bioorg Med Chem 6:1457-1468
Tonks NK (2003) PTP1B: from the sidelines to the front lines! FEBS Lett 546:140-148 Tonks NK, Neel BG (2001) Combinatorial control of the specificity of protein tyrosine phosphatases. Curr Opin Cell Biol 13:182-195 Tonks NK, Diltz CD, Fischer EH (1988a) Characterization of the major protein-tyrosine-
phosphatases of human placenta. J Biol Chem 263:6731-6737 Tonks NK, Diltz CD, Fischer EH (1988b) Purification of the major protein-tyrosine-phos-
phatases of human placenta. J Biol Chem 263:6722-6730 Urbanek RA, Suchard SJ, Steelman GB, Knappenberger KS, Sygowski LA, Veale CA, Chapdelaine MJ (2001) Potent reversible inhibitors of the protein tyrosine phosphatase CD45. J Med Chem 44:1777-1793 van der Wijk T, Blanchetot C, Overvoorde J, Den Hertog J (2003) Redox-regulated rotational coupling of receptor protein-tyrosine phosphatase alpha dimers. J Biol Chem 278:13968-13974
van Huijsduijnen RH, Bombrun A, Swinnen D (2002) Selecting protein tyrosine phosphatases as drug targets. Drug Discov Today 7:1013-1019
van Montfort RLM, Congreve M, Tisi D, Carr R, Jhoti H (2003) Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423:773-777 Vetter SW, Keng YF, Lawrence DS, Zhang ZY (2000) Assessment of protein-tyrosine phosphatase 1B substrate specificity using "inverse alanine scanning". J Biol Chem 275:2265-2268
Walchli S, Curchod ML, Gobert RP, Arkinstall S, van Huijsduijnen RH (2000) Identification of tyrosine phosphatases that dephosphorylate the insulin receptor—a brute force approach based on "substrate-trapping" mutants. J Biol Chem 275:9792-9796 Wang QP, Huang Z, Ramachandran C, Dinaut AN, Taylor SD (1998) Naphthalenebis[al-pha,alpha-difluoromethylenephosphonates] as potent inhibitors of protein-tyrosine phosphatases. Bioorg Med Chem Lett 8:345-350 Wang XY, Bergdahl K, Heijbel A, Liljebris C, Bleasdale JE (2001) Analysis of in vitro interactions of protein tyrosine phosphatase 1B with insulin receptors. Mol Cell Endocrinol 173:109-120
Wishart MJ, Dixon JE (2002) PTEN and myotubularin phosphatases: from 3-phospho-
inositide dephosphorylation to disease. Trends Cell Biol 12:579-585 Wrobel J, Sredy J, Moxham C, Dietrich A, Li ZN, Sawicki DR, Seestaller L, Wu L, Katz A, Sullivan D, Tio C, Zhang ZY (1999) PTP1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel 11-arylbenzo[b] naphtho[2,3-d]furans and 11-arylbenzo[b] naphtho [2,3-d] thiophenes. J Med Chem 42:3199-3202 Wu C, Sun M, Liu L, Zhou GW (2003) The function of the protein tyrosine phosphatase
SHP-1 in cancer. Gene 306:1-12 Xie LP, Zhang YL, Zhang ZY (2002) Design and characterization of an improved protein tyrosine phosphatase substrate-trapping mutant. Biochemistry 41:4032-4039 Xin ZL, Oost TK, Abad-Zapatero C, Hajduk PJ, Pei ZH, Szczepankiewicz BG, Hutchins CW, Ballaron SJ, Stashko MA, Lubben T, Trevillyan JM, Jirousek MR, Liu G (2003) Potent, selective inhibitors of protein tyrosine phosphatase 1B. Bioorg Med Chem Lett 13:1887-1890
Yahiro K, Niidome T, Kimura M, Hatakeyama T, Aoyagi H, Kurazono H, Imagawa K, Wada A, Moss J, Hirayama T (1999) Activation of Helicobacter pylori VacA toxin by alkaline or acid conditions increases its binding to a 250-kDa receptor protein-tyro-sine phosphatase beta. J Biol Chem 274:36693-36699 Yahiro K, Wada A, Nakayama M, Kimura T, Ogushi K, Niidome T, Aoyagi H, Yoshino K, Yonezawa K, Moss J, Hirayama T (2003) Protein-tyrosine phosphatase alpha, RPTP alpha, is a Helicobacter pylori VacA receptor. J Biol Chem 278:19183-19189 Yang J, Cheng ZL, Niu TQ, Liang XS, Zhao ZZJ, Zhou GW (2000) Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1. J Biol Chem 275:4066-4071 Ye B, Burke TR (1995) L-O-(2-malonyl)tyrosine (L-OMT) a new phosphotyrosyl mimic suitably protected for solid-phase synthesis of signal- transduction inhibitory pep-tides. Tetrahedron Lett 36:4733-4736 Ye B, Burke TR (1996) Synthesis of a difluorophosphonomethyl-containing phosphatase inhibitor designed from the X-ray structure of a ptp1b-bound ligand. Tetrahedron 52:9963-9970
Ye B, Akamatsu M, Shoelson SE, Wolf G, Giorgetti-Peraldi S, Yan X, Roller PP, Burke TR Jr (1995) L-O-(2-Malonyl)tyrosine: a new phosphotyrosyl mimetic for the preparation of Src homology 2 domain inhibitory peptides. J Med Chem 38:4270-4275 Yi TL, Pathak MK, Lindner DJ, Ketterer ME, Farver C, Borden EC (2002) Anticancer activity of sodium stibogluconate in synergy with IFNs. J Immunol 169:5978-5985
Zabolotny JM, Bence-Hanulec KK, Stricker-Krongrad A, Haj F, Wang Y, Minokoshi Y, Kim YB, Elmquist JK, Tartaglia LA, Kahn BB, Neel BG (2002) PTP1B regulates leptin signal transduction in vivo. Dev Cell 2:489-495 Zhang ZY, Lee SY (2003) PTP1B inhibitors as potential therapeutics in the treatment of type 2 diabetes and obesity. Expert Opin Investig Drugs 12:223-233 Zhang YL, Yao ZJ, Sarmiento M, Wu L, Burke TR, Zhang ZY (2000) Thermodynamic study of ligand binding to protein-tyrosine phosphatase 1B and its substrate-trapping mutants. J Biol Chem 275:34205-34212 Zhang Z-Y, MacLean D, McNamara DJ, Sawyer TK, Dixon JE (1994a) Protein tyrosine phosphatase specificity: size and phosphotyrosine positioning requirements in pep-tide substrates. Biochemistry 33:2285-2290 Zhang Z-Y, Thieme-Sefler AM, MacLean D, McNamara DJ, Dobrusin EM, Sawyer TK, Dixon JE (1993) Substrate specificity of the protein tyrosine phosphatases. Proc Natl Acad Sci USA 90:4446-4450 Zhang Z-Y, Wang YA, Dixon JE (1994b) Dissecting the catalytic mechanism of protein-ty-
rosine phosphatases. Proc Natl Acad Sci USA 91:1624-1627 Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE, Waring JF, Xie N, Wilcox D, Jacobson P, Frost L, Kroeger PE, Reilly RM, Koterski S, Opgenorth TJ, Ulrich RG, Crosby S, Butler M, Murray SF, McKay RA, Bhanot S, Monia BP, Jirousek MR (2002) PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci USA 99:1135711362
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