Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Mini-Review Article

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

Author(s): Haonan Zhang, Zhengquan Gao, Chunxiao Meng*, Xiangqian Li* and Dayong Shi*

Volume 20, Issue 11, 2020

Page: [1017 - 1030] Pages: 14

DOI: 10.2174/1389557520666200303130833

Price: $65

Abstract

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

Keywords: PTP, SHP-2, SHP-1, protein tyrosine kinases, PTKs, cancer.

« Previous Next »
Graphical Abstract

[1]
Alonso, A.; Sasin, J.; Bottini, N. Protein tyrosine phosphatases in the human genome. Cell, 2004, 117(6), 699-711.
[2]
Hunter, T.; Cooper, J.A. Protein-tyrosine kinases. Annu. Rev. Biochem., 1985, 54, 897-930.
[http://dx.doi.org/10.1146/annurev.bi.54.070185.004341] [PMID: 2992362]
[3]
Iversen, L.F.; Andersen, H.S.; Møller, 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.; Hundahl Møller, N.P. MBJARo. Steric hindrance as a basis for structure-based design of selective inhibitors of protein-tyrosine phosphatases. Biochemistry, 2001, 40(49), 14812-14820.
[http://dx.doi.org/10.1021/bi011389l] [PMID: 11732900]
[4]
Hendriks, W.J.; Elson, A.; Harroch, S.; Pulido, R.; Stoker, A.; den Hertog, J. Protein tyrosine phosphatases in health and disease. FEBS J., 2013, 280(2), 708-730.
[http://dx.doi.org/10.1111/febs.12000] [PMID: 22938156]
[5]
Li, X.; Tran, K.M.; Aziz, K.E.; Sorokin, A.V.; Chen, J.; Wang, W. Defining the protein-protein interaction network of the human protein tyrosine phosphatase family. Mol. Cell. Proteomics, 2016, 15(9), 3030-3044.
[http://dx.doi.org/10.1074/mcp.M116.060277] [PMID: 27432908]
[6]
Matozaki, T.; Murata, Y.; Saito, Y.; Okazawa, H.; Ohnishi, H. Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci., 2009, 100(10), 1786-1793.
[http://dx.doi.org/10.1111/j.1349-7006.2009.01257.x] [PMID: 19622105]
[7]
Neel, B.G.; Gu, H.; Pao, L. The 'Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci., 2003, 28(6), 284-293.
[http://dx.doi.org/10.1016/S0968-0004(03)00091-4] [PMID: 12826400]
[8]
Deb, TB; Wong, L; Salomon, DS; Zhou, G; Dixon, JE; Gutkind, JS A common requirement for the catalytic activity and both SH2 domains of SHP-2 in Mitogen-Activated Protein (MAP) kinase activation by the ErbB family of receptors. A specific role for SHP-2 in map, but not c-Jun amino-terminal kinase activation., 1998, 273(27), 16643-6.
[9]
Xie, H.; Huang, S.; Li, W.; Zhao, H.; Zhang, T.; Zhang, D. Upregulation of Src homology phosphotyrosyl phosphatase 2 (Shp2) expression in oral cancer and knockdown of Shp2 expression inhibit tumor cell viability and invasion in vitro. Oral Surg. Oral Med. Oral Pathol. Oral Radiol., 2014, 117(2), 234-242.
[http://dx.doi.org/10.1016/j.oooo.2013.10.018] [PMID: 24439919]
[10]
Meng, F.; Zhao, X.; Zhang, S. Expression and significance of SHP-2 in human papillomavirus infected cervical cancer. J. Huazhong Univ. Sci. Technolog. Med. Sci., 2012, 32(2), 247-251.
[http://dx.doi.org/10.1007/s11596-012-0044-4] [PMID: 22528229]
[11]
Zhang, X.; Lavoie, G.; Fort, L.; Huttlin, E.L.; Tcherkezian, J.; Galan, J.A.; Gu, H.; Gygi, S.P.; Carreno, S.; Roux, P.P. Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility. Mol. Cell. Biol., 2013, 33(8), 1657-1670.
[http://dx.doi.org/10.1128/MCB.01353-12] [PMID: 23401857]
[12]
Zhou, X.; Coad, J.; Ducatman, B.; Agazie, Y.M. SHP2 is up-regulated in breast cancer cells and in infiltrating ductal carcinoma of the breast, implying its involvement in breast oncogenesis. Histopathology, 2008, 53(4), 389-402.
[http://dx.doi.org/10.1111/j.1365-2559.2008.03103.x] [PMID: 18643929]
[13]
Gu, J.; Han, T.; Ma, R.H.; Zhu, Y.L.; Jia, Y.N.; Du, J.J.; Chen, Y.; Jiang, X.J.; Xie, X.D.; Guo, X. SHP2 promotes laryngeal cancer growth through the Ras/Raf/Mek/Erk pathway and serves as a prognostic indicator for laryngeal cancer. Int. J. Oncol., 2014, 44(2), 481-490.
[http://dx.doi.org/10.3892/ijo.2013.2191] [PMID: 24297342]
[14]
Wen, L.; Guo, W.; Shen, L.; Zhen, C.; Luo, Q.; Luo, X. T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice. 2016, 8(5), 7586-7597.
[15]
Andersen, J.N.; Mortensen, O.H.; Peters, G.H.; Drake, P.G.; Iversen, L.F.; Olsen, O.H.; Jansen, P.G.; Andersen, H.S.; Tonks, N.K.; Møller, N.P. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol., 2001, 21(21), 7117-7136.
[http://dx.doi.org/10.1128/MCB.21.21.7117-7136.2001] [PMID: 11585896]
[16]
Jiao, H.; Berrada, K.; Yang, W.; Tabrizi, M.; Platanias, L.C.; Yi, T. Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol. Cell. Biol., 1996, 16(12), 6985-6992.
[http://dx.doi.org/10.1128/MCB.16.12.6985] [PMID: 8943354]
[17]
Adachi, M.; Fischer, EH.; Ihle, J. Mammalian SH2-containing protein tyrosine phosphatases. Cell, 1996, 85(1), 15.
[18]
J, H; B, K; Y, W; M, T; C, L; T, P YJM. Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Cell, 1996, 16(12), 6985-6992.
[19]
Adachi, M; Fischer, EH; Ihle, J; Imai, K; Jirik, F; Neel, B Mammalian SH2-containing protein tyrosine phosphatases. 1996, 85(1), 15.
[20]
He, R.J.; Yu, Z.H.; Zhang, R.Y.; Zhang, Z.Y. Protein tyrosine phosphatases as potential therapeutic targets. Acta Pharmacol. Sin., 2014, 35(10), 1227-1246.
[http://dx.doi.org/10.1038/aps.2014.80] [PMID: 25220640]
[21]
Hof, P; Pluskey, S; Dhe-Paganon, S; Eck, MJ Shoelson, SEJC Crystal Structure of the Tyrosine Phosphatase SHP-2. 1998, 92(4), 441-50.
[http://dx.doi.org/10.1016/S0092-8674(00)80938-1]
[22]
Yu, W.M.; Guvench, O.; Mackerell, A.D.; Qu, C.K. Identification of small molecular weight inhibitors of Src homology 2 domain-containing tyrosine phosphatase 2 (SHP-2) via in silico database screening combined with experimental assay. J. Med. Chem., 2008, 51(23), 7396-7404.
[http://dx.doi.org/10.1021/jm800229d] [PMID: 19007293]
[23]
Garcia Fortanet, J.; Chen, C.H.; Chen, Y.N.; Chen, Z.; Deng, Z.; Firestone, B.; Fekkes, P.; Fodor, M.; Fortin, P.D.; Fridrich, C.; Grunenfelder, D.; Ho, S.; Kang, Z.B.; Karki, R.; Kato, M.; Keen, N.; LaBonte, L.R.; Larrow, J.; Lenoir, F.; Liu, G.; Liu, S.; Lombardo, F.; Majumdar, D.; Meyer, M.J.; Palermo, M.; Perez, L.; Pu, M.; Ramsey, T.; Sellers, W.R.; Shultz, M.D.; Stams, T.; Towler, C.; Wang, P.; Williams, S.L.; Zhang, J.H.; LaMarche, M.J. Allosteric Inhibition of SHP2: Identification of a potent, selective, and orally efficacious phosphatase inhibitor. J. Med. Chem., 2016, 59(17), 7773-7782.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00680] [PMID: 27347692]
[24]
Fodor, M.; Price, E.; Wang, P.; Lu, H.; Argintaru, A.; Chen, Z.; Glick, M.; Hao, H.X.; Kato, M.; Koenig, R.; LaRochelle, J.R.; Liu, G.; McNeill, E.; Majumdar, D.; Nishiguchi, G.A.; Perez, L.B.; Paris, G.; Quinn, C.M.; Ramsey, T.; Sendzik, M.; Shultz, M.D.; Williams, S.L.; Stams, T.; Blacklow, S.C.; Acker, M.G.; LaMarche, M.J. Dual allosteric inhibition of SHP2 phosphatase. ACS Chem. Biol., 2018, 13(3), 647-656.
[http://dx.doi.org/10.1021/acschembio.7b00980] [PMID: 29304282]
[25]
Chio, C.M.; Lim, C.S.; Bishop, A.C. Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2. Biochemistry, 2015, 54(2), 497-504.
[http://dx.doi.org/10.1021/bi5013595] [PMID: 25519989]
[26]
Liu, W.; Yu, B.; Xu, G.; Xu, W.R.; Loh, M.L.; Tang, L.D.; Qu, C.K. Identification of cryptotanshinone as an inhibitor of oncogenic protein tyrosine phosphatase SHP2 (PTPN11). J. Med. Chem., 2013, 56(18), 7212-7221.
[http://dx.doi.org/10.1021/jm400474r] [PMID: 23957426]
[27]
Wang, W.; Liu, L.; Song, X.; Mo, Y.; Komma, C.; Bellamy, H.D.; Zhao, Z.J.; Zhou, G.W. Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation. J. Cell. Biochem., 2011, 112(8), 2062-2071.
[http://dx.doi.org/10.1002/jcb.23125] [PMID: 21465528]
[28]
Yang, J.; Liu, L.; He, D.; Song, X.; Liang, X.; Zhao, Z.J.; Zhou, G.W. Crystal structure of human protein-tyrosine phosphatase SHP-1. J. Biol. Chem., 2003, 278(8), 6516-6520.
[http://dx.doi.org/10.1074/jbc.M210430200] [PMID: 12482860]
[29]
Zhang, J.; Somani, A.K.; Siminovitch, K.A. Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling. Semin. Immunol., 2000, 12(4), 361-378.
[http://dx.doi.org/10.1006/smim.2000.0223] [PMID: 10995583]
[30]
Chen, L.; Sung, S.S.; Yip, M.L.; Lawrence, H.R.; Ren, Y.; Guida, W.C.; Sebti, S.M.; Lawrence, N.J.; Wu, J. Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Mol. Pharmacol., 2006, 70(2), 562-570.
[http://dx.doi.org/10.1124/mol.106.025536] [PMID: 16717135]
[31]
Yu, Z.H.; Chen, L.; Wu, L.; Liu, S.; Wang, L.; Zhang, Z.Y. Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening. Bioorg. Med. Chem. Lett., 2011, 21(14), 4238-4242.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.078] [PMID: 21669525]
[32]
He, R.; Yu, Z.H.; Zhang, R.Y.; Wu, L.; Gunawan, A.M.; Lane, B.S.; Shim, J.S.; Zeng, L.F.; He, Y.; Chen, L.; Wells, C.D.; Liu, J.O.; Zhang, Z.Y. Exploring the existing drug space for novel pTyr mimetic and SHP2 inhibitors. ACS Med. Chem. Lett., 2015, 6(7), 782-786.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00118] [PMID: 26191366]
[33]
Lawrence, HR; Roberta, P; Liwei, C; Yunting, L; Ann Marie, S; Shen-Shu, S Inhibitors of Src homology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffolds. 2008, 51(16), 4948.
[34]
Streiber, M.; Picard, F.; Scherer, C.; Seidel, S.B.; Hartmann, R.W. Methyl esters of N-(dicyclohexyl)acetyl-piperidine-4-(benzylidene-4-carboxylic acids) as drugs and prodrugs: a new strategy for dual inhibition of 5 alpha-reductase type 1 and type 2. J. Pharm. Sci., 2005, 94(3), 473-480.
[http://dx.doi.org/10.1002/jps.20265] [PMID: 15627259]
[35]
Chen, L.; Pernazza, D.; Scott, L.M.; Lawrence, H.R.; Ren, Y.; Luo, Y.; Wu, X.; Sung, S.S.; Guida, W.C.; Sebti, S.M.; Lawrence, N.J.; Wu, J. Inhibition of cellular Shp2 activity by a methyl ester analog of SPI-112. Biochem. Pharmacol., 2010, 80(6), 801-810.
[http://dx.doi.org/10.1016/j.bcp.2010.05.019] [PMID: 20510203]
[36]
Chen, C.; Liang, F.; Chen, B.; Sun, Z.; Xue, T.; Yang, R.; Luo, D. Identification of demethylincisterol A3 as a selective inhibitor of protein tyrosine phosphatase Shp2. Eur. J. Pharmacol., 2017, 795, 124-133.
[http://dx.doi.org/10.1016/j.ejphar.2016.12.012] [PMID: 27939989]
[37]
Scott, L.M.; Chen, L.; Daniel, K.G.; Brooks, W.H.; Guida, W.C.; Lawrence, H.R.; Sebti, S.M.; Lawrence, N.J.; Wu, J. Shp2 protein tyrosine phosphatase inhibitor activity of estramustine phosphate and its triterpenoid analogs. Bioorg. Med. Chem. Lett., 2011, 21(2), 730-733.
[http://dx.doi.org/10.1016/j.bmcl.2010.11.117] [PMID: 21193311]
[38]
Qiu, W; Wang, X; Romanov, V; Hutchinson, A; Lin, A; Ruzanov, M Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 ( PTPN11 ). 2014, 14(1), 10.
[39]
Gao, Z.H.; Shi, Y.M.; Qiang, Z.; Wang, X.; Shang, S.Z.; Yang, Y.; Du, B.W.; Peng, H.P.; Ji, X.; Li, H.; Wang, F.; Xiao, W.L. Plasiatine, an unprecedented Indole-Phenylpropanoid hybrid from plantago asiatica as a potent activator of the nonreceptor protein tyrosine phosphatase Shp2. Sci. Rep., 2016, 6, 24945.
[http://dx.doi.org/10.1038/srep24945] [PMID: 27101899]
[40]
Chen, C.; Cao, M.; Zhu, S.; Wang, C.; Liang, F.; Yan, L.; Luo, D. Discovery of a novel inhibitor of the protein tyrosine phosphatase Shp2. Sci. Rep., 2015, 5, 17626.
[http://dx.doi.org/10.1038/srep17626] [PMID: 26626996]
[41]
Liu, S.; Yu, Z.; Yu, X.; Huang, S.X.; Luo, Y.; Wu, L.; Shen, W.; Yang, Z.; Wang, L.; Gunawan, A.M.; Chan, R.J.; Shen, B.; Zhang, Z.Y. SHP2 is a target of the immunosuppressant tautomycetin. Chem. Biol., 2011, 18(1), 101-110.
[http://dx.doi.org/10.1016/j.chembiol.2010.10.015] [PMID: 21276943]
[42]
Wang, W.L.; Chen, X.Y.; Gao, Y.; Gao, L.X.; Sheng, L.; Zhu, J.; Xu, L.; Ding, Z.Z.; Zhang, C.; Li, J.Y.; Li, J.; Zhou, Y.B. Benzo[c][1,2,5]thiadiazole derivatives: A new class of potent Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) inhibitors. Bioorg. Med. Chem. Lett., 2017, 27(23), 5154-5157.
[http://dx.doi.org/10.1016/j.bmcl.2017.10.059] [PMID: 29100798]
[43]
Grosskopf, S.; Eckert, C.; Arkona, C.; Radetzki, S.; Böhm, K.; Heinemann, U.; Wolber, G.; von Kries, J.P.; Birchmeier, W.; Rademann, J. 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.
[http://dx.doi.org/10.1002/cmdc.201500015] [PMID: 25877780]
[44]
Zhang, X.; He, Y.; Liu, S.; Yu, Z.; Jiang, Z.X.; Yang, Z.; Dong, Y.; Nabinger, S.C.; Wu, L.; Gunawan, A.M.; Wang, L.; Chan, R.J.; Zhang, Z.Y. Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). J. Med. Chem., 2010, 53(6), 2482-2493.
[http://dx.doi.org/10.1021/jm901645u] [PMID: 20170098]
[45]
Klaus, H; Stefanie, G; Ching Tung, L; Martin, W; Nadine, RD; Jens Peter, VK Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking. 2008, 105(20), 7225-80.
[46]
Li, J.; Kang, Y.; Wei, L.; Liu, W.; Tian, Y.; Chen, B.; Lin, X.; Li, Y.; Feng, G.S.; Lu, Z. Tyrosine phosphatase Shp2 mediates the estrogen biological action in breast cancer via interaction with the estrogen extranuclear receptor. PLoS One, 2014, 9(7) e102847
[http://dx.doi.org/10.1371/journal.pone.0102847] [PMID: 25048202]
[47]
Milne, G.W.; Feldman, A.; Miller, J.A.; Daly, G.P. Hammel MJJJoCI, Sciences C. The NCI drug information system. 2. DIS Pre-Reg., 1986, 26(4), 159-168.

Rights & Permissions Print Cite
Article Metrics
63
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy