1932

Abstract

Cancer, more than any other human disease, now has a surfeit of potential molecular targets poised for therapeutic exploitation. Currently, a number of attractive and validated cancer targets remain outside of the reach of pharmacological regulation. Some have been described as undruggable, at least by traditional strategies. In this article, we outline the basis for the undruggable moniker, propose a reclassification of these targets as undrugged, and highlight three general classes of this imposing group as exemplars with some attendant strategies currently being explored to reclassify them. Expanding the spectrum of disease-relevant targets to pharmacological manipulation is central to reducing cancer morbidity and mortality.

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2016-01-06
2024-06-20
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Literature Cited

  1. Jarvis LM. 1.  2015. The year in new drugs. Chem. Eng. News 93:11–16 [Google Scholar]
  2. Russ AP, Lampel S. 2.  2005. The druggable genome: an update. Drug Discov. Today 10:1607–10 [Google Scholar]
  3. Overington JP, Al-Lazikani B, Hopkins AL. 3.  2006. How many drug targets are there?. Nat. Rev. Drug Discov. 5:993–96 [Google Scholar]
  4. Pert CB, Snyder SH. 4.  1973. Opiate receptor: demonstration in nervous tissue. Science 179:1011–14 [Google Scholar]
  5. DeCosta BR, Rothman RB, Bykov V, Jacobson AE, Rice KC. 5.  1989. Selective and enantiospecific acylation of κ opioid receptors by (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide. Demonstration of κ receptor heterogeneity. J. Med. Chem. 32:281–83 [Google Scholar]
  6. Striessnig J, Murphy BJ, Catterall WA. 6.  1991. Dihydropyridine receptor of L-type Ca2+ channels: identification of binding domains for [3H](+)-PN200-110 and [3H]azidopine within the α1 subunit. PNAS 88:10769–73 [Google Scholar]
  7. Tsang CK, Qi H, Liu LF, Zheng XFS. 7.  2007. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov. Today 12:112–14 [Google Scholar]
  8. Bierer BE, Mattila PS, Standaert RF, Herzenberg LA, Burakoff SJ. 8.  et al. 1990. Two distinct signal transmission pathways in T lymphocytes are inhibited by complexes formed between an immunophilin and either FK506 or rapamycin. PNAS 87:9231–35 [Google Scholar]
  9. Rask-Andersen M, Masuram S, Schiöth HB. 9.  2014. The druggable genome: Evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol. 54:9–26 [Google Scholar]
  10. Tomasetti C, Marchionni L, Nowak MA, Parmigiani G, Vogelstein B. 10.  2014. Only three driver gene mutations are required for the development of lung and colorectal cancers. PNAS 112:118–23 [Google Scholar]
  11. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LAJ, Kinzler KW. 11.  2013. Cancer genome landscapes. Science 339:1546–58 [Google Scholar]
  12. Hu J, Locasale JW, Bielas JH, O'Sullivan J, Sheahan K. 12.  et al. 2013. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 31:522–29 [Google Scholar]
  13. Childs-Disney JL, Disney MD. 13.  2016. Approaches to validate and manipulate RNA targets with small molecules in cells. Annu. Rev. Pharmacol. Toxicol. 56:123–40 [Google Scholar]
  14. Bobbin ML, Rossi JJ. 14.  2016. RNA interference (RNAi)-based therapeutics: delivering on the promise?. Annu. Rev. Pharmacol. Toxicol. 56:103–22 [Google Scholar]
  15. Buckley DL, Raina K, Darricarrere N, Hines J, Gustafson JL. 15.  et al. 2015. HaloPROTACS: use of small molecule PROTACs to induce degradation of HaloTag fusion proteins. ACS Chem. Biol. 10:1831–37 [Google Scholar]
  16. Haberman Y, Amariglio N, Rechavi G, Eisenberg E. 16.  2008. Trinucleotide repeats are prevalent among cancer-related genes. Trends Genet. 24:14018 [Google Scholar]
  17. Yu S, Liang Y, Palacino J, Difiglia M, Lu B. 17.  2014. Drugging unconventional targets: insights from Huntington's disease. Trends Pharmacol. Sci. 35:53–62 [Google Scholar]
  18. Heinrich R, Neel BG, Rapoport TA. 18.  2002. Mathematical models of protein kinase signal transduction. Mol. Cell 9:957–70 [Google Scholar]
  19. MacKeigan JP, Murphy LO, Blenis J. 19.  2005. Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nat. Cell Biol. 7:591–600 [Google Scholar]
  20. 20. Pharm. Res. Manuf. Am 2014. Nearly 800 medicines and vaccines in clinical testing for cancer offer new hope to patients Rep., PhRMA, Washington, DC. http://www.phrma.org/sites/default/files/pdf/2014-cancer-report.pdf [Google Scholar]
  21. Brautigan DL. 21.  2013. Protein Ser/Thr phosphatases—the ugly ducklings of cell signalling. FEBS J. 280:324–45 [Google Scholar]
  22. De Munter S, Köhn M, Bollen M. 22.  2013. Challenges and opportunities in the development of protein phosphatase-directed therapeutics. ACS Chem. Biol. 18:36–45 [Google Scholar]
  23. Tonks NK. 23.  2013. Protein tyrosine phosphatases—from housekeeping enzymes to master regulators of signal transduction. FEBS J. 280:2346–78 [Google Scholar]
  24. Blaskovich MAT. 24.  2009. Drug discovery and protein tyrosine phosphatases. Curr. Med. Chem. 16:2095–176 [Google Scholar]
  25. Lazo JS, Wipf P. 25.  2009. Phosphatases as targets for cancer treatment. Curr. Opin. Investig. Drugs 10:1297–304 [Google Scholar]
  26. Emelyanov A, Bulavin DV. 26.  2015. Wip1 phosphatase in breast cancer. Oncogene 34:4429–38 [Google Scholar]
  27. Hayashi R, Tanoue K, Durell SR, Chatterjee DK, Jenkins LM. 27.  et al. 2011. Optimization of a cyclic peptide inhibitor of Ser/Thr phosphatase PPM1D (Wip1). Biochemistry 50:4537–49 [Google Scholar]
  28. Gilmartin AG, Faitg TH, Richter M, Groy A, Seefeld MA. 28.  et al. 2014. Allosteric Wip1 phosphatase inhibition through flap-subdomain interaction. Nat. Chem. Biol. 10:181–87 [Google Scholar]
  29. Yagi H, Chuman Y, Kozakai Y, Imagawa T, Takahashi Y. 29.  et al. 2012. A small molecule inhibitor of p53-inducible protein phosphatase PPM1D. Bioorg. Med. Chem. Lett. 22:729–32 [Google Scholar]
  30. Rayter S, Elliott R, Travers J, Rowlands MG, Richardson TB. 30.  et al. 2007. A chemical inhibitor of PPM1D that selectively kills cells overexpressing PPM1D. Oncogene 27:1036–44 [Google Scholar]
  31. Theobald B, Bonness K, Musiyenko A, Andrews JF, Urban G. 31.  et al. 2013. Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death. Mol. Cancer Res. 11:845–55 [Google Scholar]
  32. Roberge M, Tudan C, Hung SM, Harder KW, Jirik FR, Anderson H. 32.  1994. Antitumor drug fostriecin inhibits the mitotic entry checkpoint and protein phosphatases 1 and 2A. Cancer Res. 54:6115–21 [Google Scholar]
  33. Wei D, Parsels LA, Karnak D, Davis MA, Parsels JD. 33.  et al. 2013. Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair. Clin. Cancer Res. 19:4422–32 [Google Scholar]
  34. Roberts KG, Smith AM, McDougall F, Carpenter H, Horan M. 34.  et al. 2010. Essential requirement for PP2A inhibition by the oncogenic receptor c-KIT suggests PP2A reactivation as a strategy to treat c-KIT+ cancers. Cancer Res. 70:5438–47 [Google Scholar]
  35. Chen L, Luo LF, Lu J, Li L, Liu YF. 35.  et al. 2014. FTY720 induces apoptosis of M2 subtype acute myeloid leukemia cells by targeting sphingolipid metabolism and increasing endogenous ceramide levels. PLOS ONE 9:e103033 [Google Scholar]
  36. Janghorban M, Farrell AS, Allen-Petersen BL, Pelz C, Daniel CJ. 36.  et al. 2014. Targeting c-MYC by antagonizing PP2A inhibitors in breast cancer. PNAS 111:9157–62 [Google Scholar]
  37. Pippa R, Dominguez A, Christensen DJ, Moreno-Miralles I, Blanco-Prieto MJ. 37.  et al. 2014. Effect of FTY720 on the SET–PP2A complex in acute myeloid leukemia; SET binding drugs have antagonistic activity. Leukemia 28:1915–18 [Google Scholar]
  38. Perrotti D, Neviani R. 38.  2014. SETing OP449 into the PP2A-activating drug family. Clin. Cancer Res. 20:2026–28 [Google Scholar]
  39. Agarwal A, MacKenzie RJ, Pippa R, Eide CA, Oddo J. 39.  et al. 2014. Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia. Clin. Cancer Res. 20:2092–103 [Google Scholar]
  40. Julien SG, Dubé N, Hardy S, Tremblay ML. 40.  2011. Inside the human cancer tyrosine phosphatome. Nat. Rev. Cancer 11:35–49 [Google Scholar]
  41. Martin KR, Narang P, Medina-Franco JL, Meurice N, MacKeigan JP. 41.  2014. Integrating virtual and biochemical screening for protein tyrosine phosphatase inhibitor discovery. Methods 15:219–28 [Google Scholar]
  42. Lessard L, Stuible M, Tremblay ML. 42.  2010. The two faces of PTP1B in cancer. Biochim. Biophys. Acta 1804:613–19 [Google Scholar]
  43. Julien SG, Dubé N, Read M, Penney J, Paquet M. 43.  et al. 2007. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat. Genet. 39:338–46 [Google Scholar]
  44. Krishnan N, Koveal D, Miller DH, Xue B, Akshinthala SD. 44.  et al. 2014. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat. Chem. Biol. 10:558–66 [Google Scholar]
  45. Brenner AK, Reikvam H, Lavecchia A, Bruserud Ø. 45.  2014. Therapeutic targeting the cell division cycle 25 (CDC25) phosphatases in human acute myeloid leukemia—the possibility to target several kinases through inhibition of the various CDC25 isoforms. Molecules 19:1118414–47 [Google Scholar]
  46. Rosenker KMG, Paquette WD, Johnston PA, Sharlow ER, Vogt A. 46.  et al. 2015. Synthesis and biological evaluation of 3-aminoisoquinolin-1(2H)-one based inhibitors of the dual-specificity phosphatase Cdc25B. Bioorg. Med. Chem. 23:122810–18 [Google Scholar]
  47. Campbell AM, Zhang ZY. 47.  2014. Phosphatase of regenerating liver: a novel target for cancer therapy. Expert Opin. Ther. Targets 18:555–69 [Google Scholar]
  48. Sharlow ER, Wipf P, McQueeney KE, Bakan A, Lazo JS. 48.  2014. Investigational inhibitors of PTP4A3 phosphatase as antineoplastic agents. Expert Opin. Investig. Drugs 23:661–73 [Google Scholar]
  49. Guo K, Li J, Tang JP, Tan CP, Hong CW. 49.  et al. 2011. Targeting intracellular oncoproteins with antibody therapy or vaccination. Sci. Transl. Med. 3:99ra85 [Google Scholar]
  50. Guo K, Tang JP, Jie L, Al-Aidaroos AQ, Hong CW. 50.  et al. 2012. Engineering the first chimeric antibody in targeting intracellular PRL-3 oncoprotein for cancer therapy in mice. Oncotarget 3:158–71 [Google Scholar]
  51. Maehama T, Dixon JE. 51.  1999. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 9:125–28 [Google Scholar]
  52. Song MS, Salmena L, Pandolfi PP. 52.  2012. The functions and regulation of the PTEN tumour suppressor. Nat. Rev. Mol. Cell Biol. 13:283–96 [Google Scholar]
  53. Uversky VN, Davé V, Iakoucheva LM, Malaney P, Metallo SJ. 53.  et al. 2014. Pathological unfoldomics of uncontrolled chaos: intrinsically disordered proteins and human diseases. Chem. Rev. 114:6844–79 [Google Scholar]
  54. Buontempo F, Orsini E, Martins LR, Antunes I, Lonetti A. 54.  et al. 2014. Cytotoxic activity of the casein kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the unfolded protein response signaling. Leukemia 28:543–53 [Google Scholar]
  55. Martins LR, Lúcio P, Melão A, Antunes I, Cardoso BA. 55.  et al. 2014. Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia 28:178–82 [Google Scholar]
  56. Chen BJ, Wu YL, Tanaka Y, Zhang W. 56.  2014. Small molecules targeting c-Myc oncogene: promising anti-cancer therapeutics. Int. J. Biol. Sci. 10:1084–96 [Google Scholar]
  57. Prochownik EV, Vogt PK. 57.  2010. Therapeutic targeting of Myc. Genes Cancer 1:650–59 [Google Scholar]
  58. Yin X, Giap C, Lazo JS, Prochownik EV. 58.  2003. Low molecular weight inhibitors of Myc-Max interaction and function. Oncogene 22:6151–59 [Google Scholar]
  59. Stellas D, Szabolcs M, Koul S, Li Z, Polyzos A. 59.  et al. 2014. Therapeutic effects of an anti-Myc drug on mouse pancreatic cancer. J. Natl. Cancer Inst. 106:dju320 [Google Scholar]
  60. Savino M, Annibali D, Carucci N, Favuzzi E, Cole MD. 60.  et al. 2011. The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. PLOS ONE 6:e22284 [Google Scholar]
  61. Soucek L, Helmer-Citterich M, Sacco A, Jucker R, Cesareni G, Nasi S. 61.  1998. Design and properties of a Myc derivative that efficiently homodimerizes. Oncogene 17:2463–72 [Google Scholar]
  62. Soucek L, Jucker R, Panacchia L, Ricordy R, Tato F, Nasi S. 62.  2002. Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 62:3507–10 [Google Scholar]
  63. Annibali D, Whitfield JR, Favuzzi E, Jauset T, Serrano E. 63.  et al. 2014. Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis. Nat. Commun. 5:4632 [Google Scholar]
  64. Soucek L, Whitfield JR, Sodir NM, Masso-Valles D, Serrano E. 64.  et al. 2013. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 27:504–13 [Google Scholar]
  65. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J. 65.  et al. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–17 [Google Scholar]
  66. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S. 66.  et al. 2011. Targeting MYC dependence in cancer by inhibiting BET bromodomains. PNAS 108:16669–74 [Google Scholar]
  67. Jiang H, Bower KE, Beuscher IV AE, Zhou B, Bobkov AA. 67.  et al. 2009. Stabilizers of the Max homodimer identified in virtual ligand screening inhibit Myc function. Mol. Pharmacol. 76:491–502 [Google Scholar]
  68. Khoo KH, Chandra S, Verma CS, Lane DP. 68.  2014. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 13:217–36 [Google Scholar]
  69. Duffy MJ, Synnott NC, McGowan PM, Crown J, O'Connor D, Gallagher WM. 69.  2014. p53 as a target for the treatment of cancer. Cancer Treat. Rev. 40:1153–60 [Google Scholar]
  70. Chen F, Wang W, El-Deiry WS. 70.  2010. Current strategies to target p53 in cancer. Biochem. Pharmacol. 80:724–30 [Google Scholar]
  71. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. 71.  2009. Awakening guardian angels: drugging the p53 pathway. Nat. Rev. Cancer 9:862–73 [Google Scholar]
  72. Sun D, Li Z, Rew Y, Gribble M, Bartberger MD. 72.  et al. 2014. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J. Med. Chem. 57:1454–72 [Google Scholar]
  73. Wang S, Sun W, Zhao Y, McEachern D, Meaux I. 73.  et al. 2014. SAR405838: an optimized inhibitor of MDM2-p53 interaction that induces complete and durable tumor regression. Cancer Res. 74:5855–65 [Google Scholar]
  74. Zhao Y, Bernard D, Wang S. 74.  2013. Small molecule inhibitors of MDM2-p53 and MDMX-p53 interactions as new cancer therapeutics. BioDiscovery 8:4 [Google Scholar]
  75. Quintás-Cardama A, Verstovsek S. 75.  2013. Molecular pathways: JAK/STAT pathway: mutations, inhibitors, and resistance. Clin. Cancer Res. 19:1933–40 [Google Scholar]
  76. Johnston PA, Sen M, Hua Y, Camarco D, Shun TY. 76.  et al. 2014. High content pSTAT3/1 imaging assays to screen for selective inhibitors of STAT3 pathway activation in head and neck cancer cell lines. Assay Drug Dev. Technol. 12:55–79 [Google Scholar]
  77. LaPorte MG, da Paz Lima DJ, Zhang F, Sen M, Grandis JR. 77.  et al. 2014. 2-Guanidinoquinazolines as new inhibitors of the STAT3 pathway. Bioorg. Med. Chem. Lett. 24:5081–85 [Google Scholar]
  78. Don-Doncow N, Escobar Z, Johansson M, Kjellström S, Garcia V. 78.  et al. 2014. Galiellalactone is a direct inhibitor of the transcription factor STAT3 in prostate cancer cells. J. Biol. Chem. 289:15969–78 [Google Scholar]
  79. Hellsten R, Johansson M, Dahlman A, Dizeyi N, Sterner O, Bjartell A. 79.  2008. Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3. Prostate 68:269–80 [Google Scholar]
  80. Krueger AB, Drasin D, Lea WA, Patrick AN, Patnaik S. 80.  et al. 2014. Allosteric inhibitors of the Eya2 phosphatase are selective and inhibit Eya2-mediated cell migration. J. Biol. Chem. 289:16349–61 [Google Scholar]
  81. Krueger AB, Dehdashti SJ, Southall N, Marugan JJ, Ferrer M. 81.  et al. 2013. Identification of a selective small-molecule inhibitor series targeting the eyes absent 2 (Eya2) phosphatase activity. J. Biomol. Screen. 18:85–96 [Google Scholar]
  82. Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L. 82.  et al. 2015. Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science 347:779–84 [Google Scholar]
  83. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. 83.  2014. Drugging the undruggable RAS: mission possible?. Nat. Rev. Drug Discov. 13:828–51 [Google Scholar]
  84. Thompson H. 84.  2013. US National Cancer Institute's new RAS project targets an old foe. Nat. Med. 19:949–50 [Google Scholar]
  85. Chin L, Tam A, Pomerantz J, Wong M, Holash J. 85.  et al. 1998. Essential role for oncogenic Ras in tumour maintenance. Nature 400:468–72 [Google Scholar]
  86. Maurer T, Garrenton LS, Oh A, Pitts K, Anderson DJ. 86.  et al. 2012. Small-molecule ligands bind to a distinct pocket in Ras and inhibit SOS-mediated nucleotide exchange activity. PNAS 109:5299–304 [Google Scholar]
  87. Chen X, Makarewicz JM, Knauf JA, Johnson LK, Fagin JA. 87.  2014. Transformation by Hras(G12V) is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition. Oncogene 33:5442–49 [Google Scholar]
  88. Vigil D, Cherfils J, Rossman KL, Der CJ. 88.  2010. RAS superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat. Rev. Cancer 10:842–57 [Google Scholar]
  89. Laheru D, Shah P, Rajeshkumar NV, McAllister F, Taylor G. 89.  et al. 2010. Integrated preclinical and clinical development of S-trans, trans-farnesylthiosalicylic acid (FTS, Salirasib) in pancreatic cancer. Investig. New Drugs 30:3291–99 [Google Scholar]
  90. Crews CM, Buckley DL. 90.  2014. Small-molecule control of intracellular protein levels through modulation of the ubiquitin proteasome system. Angew. Chem. Int. Ed. Engl. 53:2313–30 [Google Scholar]
  91. Xie T, Lim SM, Westover KD, Dodge ME, Ercan D. 91.  et al. 2014. Pharmacological targeting of the pseudokinase Her3. Nat. Chem. Biol. 10:1006–12 [Google Scholar]
  92. Chuman Y, Yagi H, Fukuda T, Nomura T, Matsukizono M. 92.  et al. 2008. Characterization of the active site and a unique uncompetitive inhibitor of the PPM1-type protein phosphatase PPM1D. Protein Pept. Lett. 15:938–48 [Google Scholar]
  93. Liang Ma L, Wen Z-S, Liu Z, Hu Z, Ma J. 93.  et al. 2011. Overexpression and small molecule-triggered downregulation of CIP2A in lung cancer. PLOS ONE 6:5e20159 [Google Scholar]
  94. Cristóbal I, Manso R, Rincón R, Caramés C, Senin C. 94.  et al. 2014. PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol. Cancer Ther. 13:938–47 [Google Scholar]
  95. Swingle MR, Amable L, Lawhorn BG, Buck SB, Burke CP. 95.  et al. 2009. Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and (β12-β13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors. J. Pharmacol. Exp. Ther. 331:45–53 [Google Scholar]
  96. Zhang X, He Y, Liu S, Yu Z, Jiang Z-X. 96.  et al. 2010. Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). J. Med. Chem. 53:2482–93 [Google Scholar]
  97. Zeng L-F, Zhang R-Y, Yu Z-H, Sijiu Li, Wu L. 97.  et al. 2014. Therapeutic potential of targeting the oncogenic SHP2 phosphatase. J. Med. Chem. 57:6594–609 [Google Scholar]
  98. Mattila E, Marttila H, Sahlberg N, Kohonen P, Tähtinen S. 98.  et al. 2010. Inhibition of receptor tyrosine kinase signalling by small molecule agonist of T-cell protein tyrosine phosphatase. BMC Cancer 10:7 [Google Scholar]
  99. Daouti S, Li WH, Qian H, Huang KS, Holmgren J. 99.  et al. 2008. A selective phosphatase of regenerating liver phosphatase inhibitor suppresses tumor cell anchorage-independent growth by a novel mechanism involving p130Cas cleavage. Cancer Res. 68:1162–69 [Google Scholar]
  100. Min G, Lee SK, Kim HN, Han YM, Lee RH. 100.  et al. 2013. Rhodanine-based PRL-3 inhibitors blocked the migration and invasion of metastatic cancer cells. Bioorg. Med. Chem. Lett. 23:3769–74 [Google Scholar]
  101. Ortuso F, Paduano F, Carotenuto A, Gomez-Monterrey I, Bilotta A. 101.  et al. 2013. Discovery of PTPRJ agonist peptides that effectively inhibit in vitro cancer cell proliferation and tube formation. ACS Chem. Biol. 8:1497–506 [Google Scholar]
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