Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery.

Szczegóły
Abstrakt

Tytuł:: Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery.
Autorzy:: Elhassan RM; Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, China.
Hou X; Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, China.
Fang H; Department of Medicinal Chemistry and Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmacy, Shandong University, Jinan, Shandong, China.
Źródło:: Medicinal research reviews [Med Res Rev] 2022 May; Vol. 42 (3), pp. 1064-1110. Date of Electronic Publication: 2021 Nov 17.
Typ publikacji:: Journal Article; Review; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: New York : Wiley, c1981-
MeSH Terms:: Enzyme Inhibitors*/chemistry
Enzyme Inhibitors*/pharmacology
Protein Tyrosine Phosphatases*/chemistry
Protein Tyrosine Phosphatases*/metabolism
Drug Discovery ; Humans ; Signal Transduction ; Structure-Activity Relationship
References:: Yu ZH, Zhang ZY. Regulatory mechanisms and novel therapeutic targeting strategies for protein tyrosine phosphatases. Chem Rev. 2018;118(3):1069-1091.
Elson A. Stepping out of the shadows: oncogenic and tumor-promoting protein tyrosine phosphatases. Int J Biochem Cell Biol. 2018;96:135-147.
Frankson R, Yu ZH, Bai Y, Li Q, Zhang RY, Zhang ZY. Therapeutic targeting of oncogenic tyrosine phosphatases. Cancer Res. 2017;77(21):5701-5705.
Julien SG, Dube N, Hardy S, Tremblay ML. Inside the human cancer tyrosine phosphatome. Nat Rev Cancer. 2011;11(1):35-49.
Tautz L, Senis YA, Oury C, Rahmouni S. Perspective: tyrosine phosphatases as novel targets for antiplatelet therapy. Bioorg Med Chem. 2015;23(12):2786-2797.
Lauriol J, Jaffre F, Kontaridis MI. The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease. Semin Cell Dev Biol. 2015;37:73-81.
Tonks NK. Protein tyrosine phosphatases: from housekeeping enzymes to master regulators of signal transduction. FEBS J. 2013;280(2):346-378.
Roskoski R, Jr. A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res. 2015;100:1-23.
He RJ, Yu ZH, Zhang RY, Zhang ZY. Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol Sin. 2014;35(10):1227-1246.
Alonso A, Sasin J, Bottini N, et al. Protein tyrosine phosphatases in the human genome. Cell. 2004;117(6):699-711.
Tabernero L, Aricescu AR, Jones EY, Szedlacsek SE. Protein tyrosine phosphatases: structure-function relationships. FEBS J. 2008;275(5):867-82.
Guan KL, Dixon JE. Evidence for protein-tyrosine-phosphatase catalysis proceeding via a cysteine-phosphate intermediate. J Biol Chem. 1991;266(26):17026-17030.
Denu JM, Lohse DL, Vijayalakshmi J, Saper MA, Dixon JE. Visualization of intermediate and transition-state structures in protein-tyrosine phosphatase catalysis. Proc Natl Acad Sci U S A. 1996;93(6):2493-2498.
Zhang ZY, Wang Y, Dixon JE. Dissecting the catalytic mechanism of protein-tyrosine phosphatases. Proc Natl Acad Sci U S A. 1994;91(5):1624-1627.
Hengge AC, Sowa GA, Wu L, Zhang ZY. Nature of the transition state of the protein-tyrosine phosphatase-catalyzed reaction. Biochemistry. 1995;34(43):13982-13987.
Zabolotny JM, Kim YB, Welsh LA, Kershaw EE, Neel BG, Kahn BB. Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J Biol Chem. 2008;283(21):14230-14241.
Jia Z, Barford D, Flint AJ, Tonks NK. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science (New York, NY). 1995;268(5218):1754-1758.
Barford D, Flint AJ, Tonks NK. Crystal structure of human protein tyrosine phosphatase 1B. Science (New York, NY). 1994;263(5152):1397-1404.
Pedersen AK, Peters GG, Moller KB, Iversen LF, Kastrup JS. Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B. Acta Crystallogr D Biol Crystallogr. 2004;60(Pt 9):1527-1534.
Liu WS, Yang B, Wang RR, et al. Design, synthesis and biological evaluation of pyridine derivatives as selective SHP2 inhibitors. Bioorg Chem. 2020;100:103875.
Patel AD, Pasha TY, Lunagariya P, Shah U, Bhambharoliya T, Tripathi RKP. A library of thiazolidin-4-one derivatives as protein tyrosine phosphatase 1B (PTP1B) inhibitors: an attempt to discover novel antidiabetic agents. ChemMedChem. 2020;15(13):1229-1242.
Zhang ZY. Drugging the undruggable: therapeutic potential of targeting protein tyrosine phosphatases. Acc Chem Res. 2017;50(1):122-129.
Hardy JA, Wells JA. Searching for new allosteric sites in enzymes. Curr Opin Struct Biol. 2004;14(6):706-715.
Gunasekaran K, Ma B, Nussinov R. Is allostery an intrinsic property of all dynamic proteins? Proteins. 2004;57(3):433-443.
Monod J, Changeux JP, Jacob F. Allosteric proteins and cellular control systems. J Mol Biol. 1963;6:306-329.
Motlagh HN, Wrabl JO, Li J, Hilser VJ. The ensemble nature of allostery. Nature. 2014;508(7496):331-339.
Goodey NM, Benkovic SJ. Allosteric regulation and catalysis emerge via a common route. Nat Chem Biol. 2008;4(8):474-482.
Choy MS, Li Y, Machado LESF, et al. Conformational rigidity and protein dynamics at distinct timescales regulate PTP1B activity and allostery. Mol Cell. 2017;65(4):644-658.
Kamerlin SCL, Rucker R, Boresch S. A targeted molecular dynamics study of WPD loop movement in PTP1B. Biochem Biophys Res Commun. 2006;345(3):1161-1166.
Whittier SK, Hengge AC, Loria JP. Conformational motions regulate phosphoryl transfer in related protein tyrosine phosphatases. Science (New York, NY). 2013;341(6148):899-903.
Hussain H, Green IR, Abbas G, Adekenov SM, Hussain W, Ali I. Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential anti-diabetes agents: patent review (2015-2018). Expert Opin Ther Pat. 2019;29(9):689-702.
Tasker NR, Rastelli EJ, Burnett JC, Sharlow ER, Lazo JS, Wipf P. Tapping the therapeutic potential of protein tyrosine phosphatase 4A with small molecule inhibitors. Bioorg Med Chem Lett. 2019;29(16):2008-2015.
Kostrzewa T, Styszko J, Gorska-Ponikowska M, Sledzinski T, Kuban-Jankowska A. Inhibitors of protein tyrosine phosphatase PTP1B with anticancer potential. Anticancer Res. 2019;39(7):3379-3384.
Yuan X, Bu H, Zhou J, Yang CY, Zhang H. Recent advances of SHP2 inhibitors in cancer therapy: current development and clinical application. J Med Chem. 2020;63:11368-11396.
Lazo JS, McQueeney KE, Burnett JC, Wipf P, Sharlow ER. Small molecule targeting of PTPs in cancer. Int J Biochem Cell Biol. 2018;96:171-181.
Bakke J, Haj FG. Protein-tyrosine phosphatase 1B substrates and metabolic regulation. Semin Cell Dev Biol. 2015;37:58-65.
Byon JC, Kusari AB, Kusari J. Protein-tyrosine phosphatase-1B acts as a negative regulator of insulin signal transduction. Mol Cell Biochem. 1998;182(1-2):101-108.
Seely BL, Staubs PA, Reichart DR, et al. Protein tyrosine phosphatase 1B interacts with the activated insulin receptor. Diabetes. 1996;45(10):1379-1385.
Dube N, Cheng A, Tremblay ML. The role of protein tyrosine phosphatase 1B in Ras signaling. Proc Natl Acad Sci U S A. 2004;101(7):1834-1839.
Yu M, Liu Z, Liu Y, et al. PTP1B markedly promotes breast cancer progression and is regulated by miR-193a-3p. FEBS J. 2019;286(6):1136-1153.
Wang W, Cao Y, Zhou X, Wei B, Zhang Y, Liu X. PTP1B promotes the malignancy of ovarian cancer cells in a JNK-dependent mechanism. Biochem Biophys Res Commun. 2018;503(2):903-909.
Liao SC, Li JX, Yu L, Sun SR. Protein tyrosine phosphatase 1B expression contributes to the development of breast cancer. J Zhejiang Univ Sci B. 2017;18(4):334-342.
Liu X, Chen Q, Hu XG, et al. PTP1B promotes aggressiveness of breast cancer cells by regulating PTEN but not EMT. Tumour Biol. 2016;37(10):13479-13487.
Cho H. Protein tyrosine phosphatase 1B (PTP1B) and obesity. Vitam Horm. 2013;91:405-424.
Krishnan N, Konidaris KF, Gasser G, Tonks NK. A potent, selective, and orally bioavailable inhibitor of the protein-tyrosine phosphatase PTP1B improves insulin and leptin signaling in animal models. J Biol Chem. 2018;293(5):1517-1525.
Wrobel J, Sredy J, Moxham C, et al. 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. 1999;42(17):3199-3202.
Wiesmann C, Barr KJ, Kung J, et al. Allosteric inhibition of protein tyrosine phosphatase 1B. Nat Struct Mol Biol. 2004;11(8):730-737.
Kamerlin SC, Rucker R, Boresch S. A molecular dynamics study of WPD-loop flexibility in PTP1B. Biochem Biophys Res Commun. 2007;356(4):1011-1016.
Cui W, Cheng YH, Geng LL, Liang DS, Hou TJ, Ji MJ. Unraveling the allosteric inhibition mechanism of PTP1B by free energy calculation based on umbrella sampling. J Chem Inf Model. 2013;53(5):1157-1167.
Javier GM. Computational insight into the selective allosteric inhibition for PTP1B versus TCPTP: a molecular modelling study. J Biomol Struct Dyn. 2020;39:1-12.
Shinde RN, Sobhia ME. Binding and discerning interactions of PTP1B allosteric inhibitors: novel insights from molecular dynamics simulations. J Mol Graph Model. 2013;45:98-110.
Olmez EO, Alakent B. Alpha7 helix plays an important role in the conformational stability of PTP1B. J Biomol Struct Dyn. 2011;28(5):675-693.
Bharatham K, Bharatham N, Kwon YJ, Lee KW. Molecular dynamics simulation study of PTP1B with allosteric inhibitor and its application in receptor based pharmacophore modeling. J Comput Aided Mol Des. 2008;22(12):925-933.
Li S, Zhang J, Lu S, et al. The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B. PLoS One. 2014;9(5):e97668.
Shinde RN, Kumar GS, Eqbal S, Sobhia ME. Screening and identification of potential PTP1B allosteric inhibitors using in silico and in vitro approaches. PLoS One. 2018;13(6):0199020.
Zhang Z-Y, Lee S-Y. PTP1B inhibitors as potential therapeutics in the treatment of Type 2 diabetes and obesity. Expert Opin Invest Drugs. 2003;12(2):223-233.
Lantz KA, Hart SG, Planey SL, et al. Inhibition of PTP1B by trodusquemine (MSI-1436) causes fat-specific weight loss in diet-induced obese mice. Obesity (Silver Spring). 2010;18(8):1516-1523.
Krishnan N, Koveal D, Miller DH, et al. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat Chem Biol. 2014;10(7):558-566.
Maccari R, Paoli P, Ottanà R, et al. 5-Arylidene-2,4-thiazolidinediones as inhibitors of protein tyrosine phosphatases. Bioorg Med Chem. 2007;15(15):5137-5149.
Ottanà R, Maccari R, Ciurleo R, et al. 5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors. Bioorg Med Chem. 2009;17(5):1928-1937.
Maccari R, Ottanà R, Ciurleo R, et al. Structure-based optimization of benzoic acids as inhibitors of protein tyrosine phosphatase 1B and low molecular weight protein tyrosine phosphatase. ChemMedChem. 2009;4(6):957-962.
Ottanà R, Maccari R, Amuso S, et al. New 4-[(5-arylidene-2-arylimino-4-oxo-3-thiazolidinyl)methyl]benzoic acids active as protein tyrosine phosphatase inhibitors endowed with insulinomimetic effect on mouse C2C12 skeletal muscle cells. Eur J Med Chem. 2012;50:332-343.
Ottanà R, Maccari R, Mortier J, et al. Synthesis, biological activity and structure-activity relationships of new benzoic acid-based protein tyrosine phosphatase inhibitors endowed with insulinomimetic effects in mouse C2C12 skeletal muscle cells. Eur J Med Chem. 2014;71:112-127.
Ottanà R, Paoli P, Naß A, et al. Discovery of 4-[(5-arylidene-4-oxothiazolidin-3-yl)methyl]benzoic acid derivatives active as novel potent allosteric inhibitors of protein tyrosine phosphatase 1B: In silico studies and in vitro evaluation as insulinomimetic and anti-inflammatory agents. Eur J Med Chem. 2017;127:840-858.
Ruddraraju KV, Zhang ZY. Covalent inhibition of protein tyrosine phosphatases. Mol BioSyst. 2017;13(7):1257-1279.
Gehringer M, Laufer SA. Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology. J Med Chem. 2019;62(12):5673-724.
Lanning BR, Whitby LR, Dix MM, et al. A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors. Nat Chem Biol. 2014;10(9):760-767.
Niessen S, Dix MM, Barbas S, et al. Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors. Cell chemical biology. 2017;24(11):1388-1400.
Bauer RA. Covalent inhibitors in drug discovery: from accidental discoveries to avoided liabilities and designed therapies. Drug Discovery Today. 2015;20(9):1061-1073.
Hansen SK, Cancilla MT, Shiau TP, Kung J, Chen T, Erlanson DA. Allosteric inhibition of PTP1B activity by selective modification of a non-active site cysteine residue. Biochemistry. 2005;44(21):7704-7712.
Punthasee P, Laciak AR, Cummings AH, et al. Covalent allosteric inactivation of protein tyrosine phosphatase 1B (PTP1B) by an inhibitor-electrophile conjugate. Biochemistry. 2017;56(14):2051-2060.
Keedy DA, Hill ZB, Biel JT, et al. An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering. eLife. 2018;7:7.
Zargari F, Lotfi M, Shahraki O, Nikfarjam Z, Shahraki J. Flavonoids as potent allosteric inhibitors of protein tyrosine phosphatase 1B: molecular dynamics simulation and free energy calculation. J Biomol Struct Dyn. 2018;36(15):4126-4142.
Wang Y, Yuk HJ, Kim JY, et al. Novel chromenedione derivatives displaying inhibition of protein tyrosine phosphatase 1B (PTP1B) from Flemingia philippinensis. Bioorg Med Chem Lett. 2016;26(2):318-21.
Sasaki T, Li W, Higai K, Quang TH, Kim YH, Koike K. Protein tyrosine phosphatase 1B inhibitory activity of lavandulyl flavonoids from roots of Sophora flavescens. Planta Med. 2014;80(7):557-60.
Paoli P, Cirri P, Caselli A, et al. The insulin-mimetic effect of Morin: a promising molecule in diabetes treatment. Biochem Biophys Acta. 2013;1830(4):3102-11.
Kyriakou E, Schmidt S, Dodd GT, et al. Celastrol promotes weight loss in diet-induced obesity by inhibiting the protein tyrosine phosphatases PTP1B and TCPTP in the hypothalamus. J Med Chem. 2018;61(24):11144-11157.
Shi T, Wijeratne EMK, Solano C, et al. An Isoform-selective PTP1B inhibitor derived from nitrogen-atom augmentation of radicicol. Biochemistry. 2019;58(30):3225-3231.
Neel BG, Gu H, Pao L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem Sci. 2003;28(6):284-293.
Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell. 1998;92(4):441-450.
Barford D, Neel BG. Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. Structure (London, England: 1993), 1998, 6(3):249-254.
Wang RR, Liu WS, Zhou L, Ma Y, Wang RL. Probing the acting mode and advantages of RMC-4550 as an Src-homology 2 domain-containing protein tyrosine phosphatase (SHP2) inhibitor at molecular level through molecular docking and molecular dynamics. J Biomol Struct Dyn. 2020;38(5):1525-1538.
Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34(2):148-150.
Chan G, Kalaitzidis D, Neel BG. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 2008;27(2):179-192.
Miyamoto D, Miyamoto M, Takahashi A, et al. Isolation of a distinct class of gain-of-function SHP-2 mutants with oncogenic RAS-like transforming activity from solid tumors. Oncogene. 2008;27(25):3508-3515.
Grossmann KS, Rosario M, Birchmeier C, Birchmeier W. The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res. 2010;106:53-89.
Ran H, Tsutsumi R, Araki T, Neel BG. Sticking it to cancer with molecular glue for SHP2. Cancer Cell. 2016;30(2):194-196.
Li J, Jie HB, Lei Y, et al. PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res. 2015;75(3):508-518.
Wang Y, Mohseni M, Grauel A, et al. SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms. Sci Rep. 2021;11(1):1399.
Gelb BD, Tartaglia M. Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet. 2006;15 Spec No 2:R220-R226.
LaRochelle JR, Fodor M, Ellegast JM, et al. Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2. Bioorg Med Chem. 2017;25(24):6479-6485.
Bagdanoff JT, Chen Z, Acker M, et al. Optimization of fused bicyclic allosteric SHP2 inhibitors. J Med Chem. 2019;62(4):1781-1792.
Nagata N, Matsuo K, Bettaieb A, et al. Hepatic Src homology phosphatase 2 regulates energy balance in mice. Endocrinology. 2012;153(7):3158-3169.
Matsuo K, Delibegovic M, Matsuo I, et al. Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. J Biol Chem. 2010;285(51):39750-39758.
Scott LM, Chen L, Daniel KG, et al. Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs. Bioorg Med Chem Lett. 2011;21(2):730-733.
Grosskopf S, Eckert C, Arkona C, et al. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem. 2015;10(5):815-826.
He R, Yu ZH, Zhang RY, et al. Exploring the existing drug space for novel pTyr mimetic and SHP2 inhibitors. ACS Med Chem Lett. 2015;6(7):782-786.
Hellmuth K, Grosskopf S, Lum CT, et al. Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking. Proc Natl Acad Sci U S A. 2008;105(20):7275-7280.
Zeng LF, Zhang RY, Yu ZH, et al. Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J Med Chem. 2014;57(15):6594-6609.
Garcia Fortanet J, Chen CHT, Chen YNP, et al. Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor. J Med Chem. 2016;59(17):7773-7782.
Chen YN, LaMarche MJ, Chan HM, et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature. 2016;535(7610):148-152.
Liu WS, Jin WY, Zhou L, et al. Structure based design of selective SHP2 inhibitors by De novo design, synthesis and biological evaluation. J Comput Aided Mol Des. 2019;33(8):759-774.
Nichols RJ, Haderk F, Stahlhut C, et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat Cell Biol. 2018;20(9):1064-1073.
Fodor M, Price E, Wang P, et al. Dual allosteric inhibition of SHP2 phosphatase. ACS Chem Biol. 2018;13(3):647-656.
Bagdanoff JT, Chen Z, Acker M, et al. Correction to optimization of fused bicyclic allosteric SHP2 inhibitors. J Med Chem. 2019;62(7):3780.
Sarver P, Acker M, Bagdanoff JT, et al. 6-Amino-3-methylpyrimidinones as potent, selective, and orally efficacious SHP2 inhibitors. J Med Chem. 2019;62(4):1793-1802.
Sarver P, Acker M, Bagdanoff JT, et al. Correction to 6-amino-3-methylpyrimidinones as potent, selective, and orally efficacious SHP2 inhibitors. J Med Chem. 2019;62(7):3781.
Xie J, Si X, Gu S, et al. Allosteric inhibitors of SHP2 with therapeutic potential for cancer treatment. J Med Chem. 2017;60(24):10205-10219.
Chen X, Zou F, Hu Z, et al. PCC0208023, a potent SHP2 allosteric inhibitor, imparts an antitumor effect against KRAS mutant colorectal cancer. Toxicol Appl Pharmacol. 2020;398:115019.
Chen CH-T, Chen Z, Dore M, et al. N-azaspirocycloalkane substituted N-heteroaryl compounds and compositions for inhibiting the activity of SHP2. Google Patents, 2019.
Wu X, Xu G, Li X, et al. Small molecule inhibitor that stabilizes the autoinhibited conformation of the oncogenic tyrosine phosphatase SHP2. J Med Chem. 2019;62(3):1125-1137.
Chio CM, Lim CS, Bishop AC. Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2. Biochemistry. 2015;54(2):497-504.
Marsh-Armstrong B, Fajnzylber JM, Korntner S, Plaman BA, Bishop AC. The allosteric site on SHP2's protein tyrosine phosphatase domain is targetable with druglike small molecules. ACS Omega. 2018;3(11):15763-15770.
Tang K, Jia YN, Yu B, Liu HM. Medicinal chemistry strategies for the development of protein tyrosine phosphatase SHP2 inhibitors and PROTAC degraders. Eur J Med Chem. 2020;204:112657.
McCoull W, Cheung T, Anderson E, et al. Development of a novel B-cell lymphoma 6 (BCL6) PROTAC to provide insight into small molecule targeting of BCL6. ACS Chem Biol. 2018;13(11):3131-3141.
Qin C, Hu Y, Zhou B, et al. Discovery of QCA570 as an exceptionally potent and efficacious proteolysis targeting chimera (PROTAC) degrader of the bromodomain and extra-terminal (BET) proteins capable of inducing complete and durable tumor regression. J Med Chem. 2018;61(15):6685-6704.
Zhou H, Bai L, Xu R, et al. Structure-based discovery of SD-36 as a potent, selective, and efficacious PROTAC degrader of STAT3 protein. J Med Chem. 2019;62(24):11280-300.
Wang Y, Jiang X, Feng F, Liu W, Sun H. Degradation of proteins by PROTACs and other strategies. Acta Pharm Sin B. 2020;10(2):207-238.
Wang M, Lu J, Wang M, Yang CY, Wang S. Discovery of SHP2-D26 as a first, potent, and effective PROTAC degrader of SHP2 protein. J Med Chem. 2020;63(14):7510-7528.
Gjorloff-Wingren A, Saxena M, Williams S, Hammi D, Mustelin T. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol. 1999;29(12):3845-3854.
Fousteri G, Liossis SN, Battaglia M. Roles of the protein tyrosine phosphatase PTPN22 in immunity and autoimmunity. Clin Immunol. 2013;149(3):556-565.
Vang T, Miletic AV, Arimura Y, Tautz L, Rickert RC, Mustelin T. Protein tyrosine phosphatases in autoimmunity. Annu Rev Immunol. 2008;26:29-55.
Bottini N, Peterson EJ. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu Rev Immunol. 2014;32:83-119.
Wu J, Katrekar A, Honigberg LA, et al. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem. 2006;281(16):11002-11010.
Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36(4):337-338.
Vang T, Congia M, Macis MD, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37(12):1317-1319.
Mustelin T, Bottini N, Stanford SM. The contribution of PTPN22 to rheumatic disease. Arthritis Rheumatol. 2019;71(4):486-495.
Brownlie RJ, Zamoyska R, Salmond RJ. Regulation of autoimmune and anti-tumour T-cell responses by PTPN22. Immunology. 2018;154(3):377-382.
Carmona FD, Martin J. The potential of PTPN22 as a therapeutic target for rheumatoid arthritis. Expert Opin Ther Targets. 2018;22(10):879-891.
Abbasifard M, Imani D, Bagheri-Hosseinabadi Z. PTPN22 gene polymorphism and susceptibility to rheumatoid arthritis (RA): updated systematic review and meta-analysis. J Gene Med. 2020;22(9):e3204.
Zheng J, Petersen F, Yu X. The role of PTPN22 in autoimmunity: learning from mice. Autoimmun Rev. 2014;13(3):266-271.
Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004;75(3):504-507.
Yu X, Sun JP, He Y, et al. Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc Natl Acad Sci U S A. 2007;104(50):19767-19772.
Liang X, Fu H, Xiao P, Fang H, Hou X. Design, synthesis and biological evaluation of imidazolidine-2,4-dione and 2-thioxothiazolidin-4-one derivatives as lymphoid-specific tyrosine phosphatase inhibitors. Bioorg Chem. 2020;103:104124.
Wu B, Guo BM, Kang J, et al. PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms. Apoptosis. 2016;21(3):365-378.
Deng K, Liu L, Tan X, et al. WIP1 promotes cancer stem cell properties by inhibiting p38 MAPK in NSCLC. Signal Transduct Target Ther. 2020;5(1):36.
Richter M, Dayaram T, Gilmartin AG, et al. WIP1 phosphatase as a potential therapeutic target in neuroblastoma. PLoS One. 2015;10(2):e0115635.
Gilmartin AG, Faitg TH, Richter M, et al. Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat Chem Biol. 2014;10(3):181-187.
Boutros T, Chevet E, Metrakos P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 2008;60(3):261-310.
Farooq A, Zhou MM. Structure and regulation of MAPK phosphatases. Cellular Signalling. 2004;16(7):769-779.
Lang R, Raffi FAM. Dual-specificity phosphatases in immunity and infection: an update. Int J Mol Sci. 2019;20(11):2710.
Pearson RB, Kemp BE. Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations. Methods Enzymol. 1991;200:62-81.
Stanford SM, Krishnamurthy D, Falk MD, et al. Discovery of a novel series of inhibitors of lymphoid tyrosine phosphatase with activity in human T cells. J Med Chem. 2011;54(6):1640-1654.
Vang T, Xie Y, Liu WH, et al. Inhibition of lymphoid tyrosine phosphatase by benzofuran salicylic acids. J Med Chem. 2011;54(2):562-571.
Li K, Hou X, Li R, et al. Identification and structure-function analyses of an allosteric inhibitor of the tyrosine phosphatase PTPN22. J Biol Chem. 2019;294(21):8653-8663.
Hou X, Li R, Li K, Yu X, Sun J-P, Fang H. Fast identification of novel lymphoid tyrosine phosphatase inhibitors using target-ligand interaction-based virtual screening. J Med Chem. 2014;57(22):9309-9322.
Andersen JN, Mortensen OH, Peters GH, et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol Cell Biol. 2001;21(21):7117-7136.
Tautz L, Critton DA, Grotegut S. Protein tyrosine phosphatases: structure, function, and implication in human disease. Methods Mol Biol. 2013;1053:179-221.
Vezzalini M, Mombello A, Menestrina F, et al. Expression of transmembrane protein tyrosine phosphatase gamma (PTPgamma) in normal and neoplastic human tissues. Histopathology. 2007;50(5):615-628.
Müller S, Kunkel P, Lamszus K, et al. A role for receptor tyrosine phosphatase zeta in glioma cell migration. Oncogene. 2003;22(43):6661-6668.
Ulbricht U, Brockmann MA, Aigner A, et al. Expression and function of the receptor protein tyrosine phosphatase zeta and its ligand pleiotrophin in human astrocytomas. J Neuropathol Exp Neurol. 2003;62(12):1265-1275.
Patel AP, Tirosh I, Trombetta JJ, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science (New York, NY). 2014;344(6190):1396-1401.
Fujikawa A, Sugawara H, Tanaka T, et al. Targeting PTPRZ inhibits stem cell-like properties and tumorigenicity in glioblastoma cells. Sci Rep. 2017;7(1):5609.
Ulbricht U, Eckerich C, Fillbrandt R, Westphal M, Lamszus K. RNA interference targeting protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta suppresses glioblastoma growth in vitro and in vivo. J Neurochem. 2006;98(5):1497-1506.
Foehr ED, Lorente G, Kuo J, Ram R, Nikolich K, Urfer R. Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model. Cancer Res. 2006;66(4):2271-2278.
Fujikawa A, Nagahira A, Sugawara H, et al. Small-molecule inhibition of PTPRZ reduces tumor growth in a rat model of glioblastoma. Sci Rep. 2016;6:20473.
Hermiston ML, Xu Z, Weiss A. CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol. 2003;21:107-137.
Desai DM, Sap J, Silvennoinen O, Schlessinger J, Weiss A. The catalytic activity of the CD45 membrane-proximal phosphatase domain is required for TCR signaling and regulation. EMBO J. 1994;13(17):4002-4010.
Nam HJ, Poy F, Saito H, Frederick CA. Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J Exp Med. 2005;201(3):441-452.
Shiroo M, Goff L, Biffen M, Shivnan E, Alexander D. CD45 tyrosine phosphatase-activated p59fyn couples the T cell antigen receptor to pathways of diacylglycerol production, protein kinase C activation and calcium influx. EMBO J. 1992;11(13):4887-4897.
Cahir McFarland ED, Hurley TR, Pingel JT, Sefton BM, Shaw A, Thomas ML. Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor. Proc Natl Acad Sci U S A. 1993;90(4):1402-1406.
Alexander DR. The CD45 tyrosine phosphatase: a positive and negative regulator of immune cell function. Semin Immunol. 2000;12(4):349-359.
Tchilian EZ, Beverley PC. Altered CD45 expression and disease. Trends Immunol. 2006;27(3):146-153.
Jacobsen M, Schweer D, Ziegler A, et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nat Genet. 2000;26(4):495-499.
Schwinzer R, Witte T, Hundrieser J, et al. Enhanced frequency of a PTPRC (CD45) exon A mutation (77C-->G) in systemic sclerosis. Genes Immun. 2003;4(2):168-169.
Vogel A, Strassburg CP, Manns MP. 77 C/G mutation in the tyrosine phosphatase CD45 gene and autoimmune hepatitis: evidence for a genetic link. Genes Immun. 2003;4(1):79-81.
Perron MD, Chowdhury S, Aubry I, Purisima E, Tremblay ML, Saragovi HU. Allosteric noncompetitive small molecule selective inhibitors of CD45 tyrosine phosphatase suppress T-cell receptor signals and inflammation in vivo. Mol Pharmacol. 2014;85(4):553-563.
Perron M, Saragovi HU. Inhibition of CD45 phosphatase activity induces cell cycle arrest and apoptosis of CD45(+) lymphoid tumors ex vivo and in vivo. Mol Pharmacol. 2018;93(6):575-580.
Goebel-Goody SM, Baum M, Paspalas CD, et al. Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. Pharmacol Rev. 2012;64(1):65-87.
Kurup P, Zhang Y, Xu J, et al. Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61. J Neurosci. 2010;30(17):5948-5957.
Sharma E, Zhao F, Bult A, Lombroso PJ. Identification of two alternatively spliced transcripts of STEP: a subfamily of brain-enriched protein tyrosine phosphatases. Brain Res Mol Brain Res. 1995;32(1):87-93.
Barr AJ, Ugochukwu E, Lee WH, et al. Large-scale structural analysis of the classical human protein tyrosine phosphatome. Cell. 2009;136(2):352-363.
Karasawa T, Lombroso PJ. Disruption of striatal-enriched protein tyrosine phosphatase (STEP) function in neuropsychiatric disorders. Neurosci Res. 2014;89:1-9.
Zhang Y, Kurup P, Xu J, et al. Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model. Proc Natl Acad Sci U S A. 2010;107(44):19014-19019.
Kurup PK, Xu J, Videira RA, et al. STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson's disease. Proc Natl Acad Sci U S A. 2015;112(4):1202-1207.
Carty NC, Xu J, Kurup P, et al. The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications. Transl Psychiatry. 2012;2:e137.
Reinhart VL, Nguyen T, Gerwien R, Jr., Kuhn M, Yates PD, Lanz TA. Downstream effects of striatal-enriched protein tyrosine phosphatase reduction on RNA expression in vivo and in vitro. Neuroscience. 2014;278:62-69.
Tautermann CS, Binder F, Büttner FH, et al. Allosteric activation of striatal-enriched protein tyrosine phosphatase (STEP, PTPN5) by a fragment-like molecule. J Med Chem. 2019;62(1):306-316.
Wei M, Korotkov KV, Blackburn JS. Targeting phosphatases of regenerating liver (PRLs) in cancer. Pharmacol Ther. 2018;190:128-138.
Ming J, Liu N, Gu Y, Qiu X, Wang EH. PRL-3 facilitates angiogenesis and metastasis by increasing ERK phosphorylation and up-regulating the levels and activities of Rho-A/C in lung cancer. Pathology. 2009;41(2):118-126.
Zimmerman MW, McQueeney KE, Isenberg JS, et al. Protein-tyrosine phosphatase 4A3 (PTP4A3) promotes vascular endothelial growth factor signaling and enables endothelial cell motility. J Biol Chem. 2014;289(9):5904-5913.
Bai Y, Luo Y, Liu S, et al. PRL-1 protein promotes ERK1/2 and RhoA protein activation through a non-canonical interaction with the Src homology 3 domain of p115 Rho GTPase-activating protein. J Biol Chem. 2011;286(49):42316-42324.
Duciel L, Anezo O, Mandal K, et al. Protein tyrosine phosphatase 4A3 (PTP4A3/PRL-3) promotes the aggressiveness of human uveal melanoma through dephosphorylation of CRMP2. Sci Rep. 2019;9(1):2990.
Zhou J, Wang S, Lu J, Li J, Ding Y. Over-expression of phosphatase of regenerating liver-3 correlates with tumor progression and poor prognosis in nasopharyngeal carcinoma. Int J Cancer. 2009;124(8):1879-1886.
Yamashita S, Masuda Y, Matsumoto K, et al. Down-regulation of the human PRL-3 gene is associated with the metastasis of primary non-small cell lung cancer. Ann Thorac Cardiovasc Surg. 2007;13(4):236-239.
Miskad UA, Semba S, Kato H, et al. High PRL-3 expression in human gastric cancer is a marker of metastasis and grades of malignancies: an in situ hybridization study. Virchows Arch. 2007;450(3):303-310.
Qu S, Liu B, Guo X, et al. Independent oncogenic and therapeutic significance of phosphatase PRL-3 in FLT3-ITD-negative acute myeloid leukemia. Cancer. 2014;120(14):2130-2141.
Park JE, Yuen HF, Zhou JB, et al. Oncogenic roles of PRL-3 in FLT3-ITD induced acute myeloid leukaemia. EMBO Mol Med. 2013;5(9):1351-1366.
Zhou J, Cheong LL, Liu SC, et al. The pro-metastasis tyrosine phosphatase, PRL-3 (PTP4A3), is a novel mediator of oncogenic function of BCR-ABL in human chronic myeloid leukemia. Mol Cancer. 2012;11:72.
Salamoun JM, McQueeney KE, Patil K, et al. Photooxygenation of an amino-thienopyridone yields a more potent PTP4A3 inhibitor. Org Biomol Chem. 2016;14(27):6398-6402.
Daouti S, Li W, Qian H, et al. A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. Cancer Res. 2008;68(4):1162-1169.
McQueeney KE, Salamoun JM, Burnett JC, et al. Targeting ovarian cancer and endothelium with an allosteric PTP4A3 phosphatase inhibitor. Oncotarget. 2018;9(9):8223-8240.
Zhou H, Zhang L, Vartuli RL, Ford HL, Zhao R. The Eya phosphatase: its unique role in cancer. Int J Biochem Cell Biol. 2018;96:165-170.
Rebay I. Multiple functions of the Eya phosphotyrosine phosphatase. Mol Cell Biol. 2015;36(5):668-677.
Blevins MA, Towers CG, Patrick AN, Zhao R, Ford HL. The SIX1-EYA transcriptional complex as a therapeutic target in cancer. Expert Opin Ther Targets. 2015;19(2):213-225.
Liu Y, Han N, Zhou S, et al. The DACH/EYA/SIX gene network and its role in tumor initiation and progression. Int J Cancer. 2016;138(5):1067-1075.
Okabe Y, Sano T, Nagata S. Regulation of the innate immune response by threonine-phosphatase of Eyes absent. Nature. 2009;460(7254):520-524.
Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426(6964):247-254.
Jung SK, Jeong DG, Chung SJ, et al. Crystal structure of ED-Eya2: insight into dual roles as a protein tyrosine phosphatase and a transcription factor. FASEB J. 2010;24(2):560-569.
Patrick AN, Cabrera JH, Smith AL, Chen XS, Ford HL, Zhao R. Structure-function analyses of the human SIX1-EYA2 complex reveal insights into metastasis and BOR syndrome. Nat Struct Mol Biol. 2013;20(4):447-453.
Krueger AB, Drasin DJ, Lea WA, et al. Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated cell migration. J Biol Chem. 2014;289(23):16349-16361.
Seifried A, Schultz J, Gohla A. Human HAD phosphatases: structure, mechanism, and roles in health and disease. FEBS J. 2013;280(2):549-571.
Li CM, Guo M, Borczuk A, et al. Gene expression in Wilms' tumor mimics the earliest committed stage in the metanephric mesenchymal-epithelial transition. Am J Pathol. 2002;160(6):2181-2190.
Behbakht K, Qamar L, Aldridge CS, et al. Six1 overexpression in ovarian carcinoma causes resistance to TRAIL-mediated apoptosis and is associated with poor survival. Cancer Res. 2007;67(7):3036-3042.
Farabaugh SM, Micalizzi DS, Jedlicka P, Zhao R, Ford HL. Eya2 is required to mediate the pro-metastatic functions of Six1 via the induction of TGF-beta signaling, epithelial-mesenchymal transition, and cancer stem cell properties. Oncogene. 2012;31(5):552-562.
Wang QF, Wu G, Mi S, et al. MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome. Blood. 2011;117(25):6895-6905.
Miller SJ, Lan ZD, Hardiman A, et al. Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene. 2010;29(3):368-379.
Auvergne RM, Sim FJ, Wang S, et al. Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes. Cell Rep. 2013;3(6):2127-2141.
Li Z, Qiu R, Qiu X, Tian T. EYA2 promotes lung cancer cell proliferation by downregulating the expression of PTEN. Oncotarget. 2017;8(67):110837-110848.
Liang Y, Xu X, Wang T, et al. The EGFR/miR-338-3p/EYA2 axis controls breast tumor growth and lung metastasis. Cell Death Dis. 2017;8(7):e2928.
Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature. 2009;458(7238):591-596.
Krueger AB, Dehdashti SJ, Southall N, et al. Identification of a selective small-molecule inhibitor series targeting the eyes absent 2 (Eya2) phosphatase activity. J Biomol Screen. 2013;18(1):85-96.
Anantharajan J, Zhou H, Zhang L, et al. Structural and functional analyses of an allosteric EYA2 phosphatase inhibitor that has on-target effects in human lung cancer cells. Mol Cancer Ther. 2019;18(9):1484-1496.
Fiscella M, Zhang H, Fan S, et al. Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. Proc Nat Acad Sci U S A. 1997;94(12):6048-6053.
Chew J, Biswas S, Shreeram S, et al. WIP1 phosphatase is a negative regulator of NF-kappaB signalling. Nat Cell Biol. 2009;11(5):659-666.
Lowe J, Cha H, Lee MO, Mazur SJ, Appella E, Fornace AJ, Jr. Regulation of the Wip1 phosphatase and its effects on the stress response. Front Biosci (Landmark edition). 2012;17:1480-1498.
Lu X, Nguyen TA, Moon SH, Darlington Y, Sommer M, Donehower LA. The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev. 2008;27(2):123-135.
Bai F, Zhou H, Fu Z, Xie J, Hu Y, Nie S. NF-kappaB-induced WIP1 expression promotes colorectal cancer cell proliferation through mTOR signaling. Biomed Pharmacother. 2018;99:402-410.
Okudela K, Yazawa T, Woo T, et al. Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis. Am J Pathol. 2009;175(2):867-881.
Furukawa T, Sunamura M, Motoi F, Matsuno S, Horii A. Potential tumor suppressive pathway involving DUSP6/MKP-3 in pancreatic cancer. Am J Pathol. 2003;162(6):1807-1815.
Keyse SM. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008;27(2):253-261.
Arkell RS, Dickinson RJ, Squires M, Hayat S, Keyse SM, Cook SJ. DUSP6/MKP-3 inactivates ERK1/2 but fails to bind and inactivate ERK5. Cell Signal. 2008;20(5):836-843.
Kawakami Y, Rodríguez-León J, Koth CM, et al. MKP3 mediates the cellular response to FGF8 signalling in the vertebrate limb. Nat Cell Biol. 2003;5(6):513-519.
Li C, Scott DA, Hatch E, Tian X, Mansour SL. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Development. 2007;134(1):167-176.
Choi WY, Gemberling M, Wang J, et al. In vivo monitoring of cardiomyocyte proliferation to identify chemical modifiers of heart regeneration. Development. 2013;140(3):660-666.
Purcell NH, Wilkins BJ, York A, et al. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Proc Natl Acad Sci U S A. 2007;104(35):14074-14079.
Missinato MA, Saydmohammed M, Zuppo DA, et al. Dusp6 attenuates Ras/MAPK signaling to limit zebrafish heart regeneration. Development. 2018;145(5):dev157206.
Vo AH, Swaggart KA, Woo A, et al. Dusp6 is a genetic modifier of growth through enhanced ERK activity. Hum Mol Genet. 2018;28(2):279-89.
Molina G, Vogt A, Bakan A, et al. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat Chem Biol. 2009;5(9):680-687.
Camps M, Nichols A, Gillieron C, et al. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science (New York, NY). 1998;280(5367):1262-1265.
Korotchenko VN, Saydmohammed M, Vollmer LL, et al. In vivo structure-activity relationship studies support allosteric targeting of a dual specificity phosphatase. ChemBioChem. 2014;15(10):1436-1445.
Contributed Indexing:: Keywords: allosteric modulators; allosteric site; protein tyrosine phosphatase
Substance Nomenclature:: 0 (Enzyme Inhibitors)
EC 3.1.3.48 (Protein Tyrosine Phosphatases)
Entry Date(s):: Date Created: 20211118 Date Completed: 20220407 Latest Revision: 20220525
Update Code:: 20240105
DOI:: 10.1002/med.21871
PMID:: 34791703
: Czasopismo naukowe

Full Text Finder

Protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation which affects a myriad of cellular processes. Imbalance in signal pathways mediated by PTPs has been associated with development of many human diseases including cancer, metabolic, and immunological diseases. Several compelling evidence suggest that many members of PTP family are novel therapeutic targets. However, the clinical development of conventional PTP-based active-site inhibitors originally was hampered by the poor selectivity and pharmacokinetic properties. In this regard, PTPs has been widely dismissed as "undruggable." Nonetheless, allosteric modulation has become increasingly an influential and alternative approach that can be exploited for drug development against PTPs. Unlike active-site inhibitors, allosteric inhibitors exhibit a remarkable target-selectivity, drug-likeness, potency, and in vivo activity. Intriguingly, there has been a high interest in novel allosteric PTPs inhibitors within the last years. In this review, we focus on the recent advances of allosteric inhibitors that have been explored in drug discovery and have shown an excellent result in the development of PTPs-based therapeutics. A special emphasis is placed on the structure-activity relationship and molecular mechanistic studies illustrating applications in chemical biology and medicinal chemistry.
(© 2021 Wiley Periodicals LLC.)

Informacja