Signal transducer and activator of transcription 3 (STAT3): A promising target for anticancer therapy

Future Medicinal Chemistry

Volumn 3, Issue 5, 2011, Pages 567-597

  Masciocchi, Daniela ^a   Gelain, Arianna ^a   Villa, Stefania ^a   Meneghetti, Fiorella ^a   Barlocco, Daniela ^a  

^a UNIVERSITY OF MILAN   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

5,15 DIPHENYLPORPHYRIN; ANTINEOPLASTIC AGENT; CATECHOL DERIVATIVE; CLT 005; CPA 1; CPA 3; CPA 7; CPD 188; CRYPTOTANSHINONE; IS 3295; ISS 221; ISS 355; ISS 363; ISS 493; ISS 610; ISS 637; LLL 12; PEPTIDE DERIVATIVE; PLATINUM DERIVATIVE; PORPHYRIN DERIVATIVE; PURINE DERIVATIVE; S 31 V 3 32; S 31 V 4 01; S 3I 201; S 3I M 2001; STA 21; STAT3 PROTEIN; STX 0119; UNCLASSIFIED DRUG; UNINDEXED DRUG; WP 1066;

AMINO ACID COMPOSITION; AMINO ACID SEQUENCE; AMINO ACID SUBSTITUTION; ANTINEOPLASTIC ACTIVITY; BREAST TUMOR; CANCER CELL DESTRUCTION; CANCER CHEMOTHERAPY; CHEMICAL MODIFICATION; DRUG POTENCY; DRUG PROTEIN BINDING; GENE EXPRESSION REGULATION; GENE OVEREXPRESSION; GLIOBLASTOMA; HUMAN; IC 50; IMMUNOLOGICAL TOLERANCE; MOLECULARLY TARGETED THERAPY; NONHUMAN; PATENT; PRIORITY JOURNAL; PROTEIN DOMAIN; PROTEIN FUNCTION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION; TUMOR ESCAPE; TUMOR PROMOTION; TUMOR VASCULARIZATION;

ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; MODELS, MOLECULAR; NEOPLASMS; SIGNAL TRANSDUCTION; STAT3 TRANSCRIPTION FACTOR;

EID: 79955623599     PISSN: 17568919     EISSN: None     Source Type: Journal    
DOI: 10.4155/fmc.11.22     Document Type: Review

References (199)

1. Darnell JE Jr. STATs and gene regulation. Science 277, 1630-1635 (1997). (Pubitemid 27446219)
2. Bromberg J, Darnell JE. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468-2473 (2000). (Pubitemid 30339202)
3. Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat. Rev. Cancer 2, 740-749 (2002) (Pubitemid 37328909)
4. Yu H, Jove R. The STATs of cancer - new molecular targets come of age. Nat. Rev. Cancer 4, 97-105 (2004). (Pubitemid 38198738)
5. Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. J. Cell Sci. 113(Pt. 16), 2813-2819 (2000).
6. Isomoto H, Mott JL, Kobayashi S. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 132(1), 384-396 (2007). (Pubitemid 46108750)
7. Shuai K. Modulation of STAT signaling by STAT-interacting proteins. Oncogene 21, 2638-2644 (2000). (Pubitemid 30339220)
8. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat. Rev. Immunol. 5, 593-605 (2005). (Pubitemid 41113191)
9. Yasukawa H, Sasaki A, Yoshimura A. Negative regulation of cytokine signaling pathways. Annu. Rev. Immunol. 18, 143-164 (2000). (Pubitemid 30365377)
10. Daino H, Matsumura I, Takada K et al. Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells: possible involvement of STAT3 degradation by proteasome pathway in interleukin 6-dependent hematopoietic cells. Blood 95, 2577-2585 (2000). (Pubitemid 30210536)
11. Yamada S, Shiono S, Joo A, Yoshimura A. Control mechanism of JAK/STAT signal transduction pathway. FEBS Lett. 534, 190-196 (2003). (Pubitemid 36084541)
12. Woetmann A, Nielsen M, Christensen ST et al. Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3. Proc. Natl Acad. Sci. 96, 10620-10625 (1999). (Pubitemid 29442193)
13. Tanaka T, Soriano MA, Grusby MJ. SLIM is a nuclear ubiquitin E3 ligase that negatively regulates STAT signaling. Immunity 22, 729-736 (2005). (Pubitemid 40814503)
14. Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the post translational level. Mol. Cell. Biol. 13, 276-288 (1993). (Pubitemid 23006905)
15. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signaling through the gp130/Jak/ STAT pathway. Biochem. J. 334, 297-314 (1998). (Pubitemid 28448572)
16. Hirano T, Ishihara K, Hibi M. Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19, 2548-2556 (2000). (Pubitemid 30339210)
17. Zhang Z, Fuller GM. The competitive binding of STAT3 and NF-kB on an overlapping DNA binding site. Biochem. Biophys. Res. Commun. 237, 90-94 (1997). (Pubitemid 27390329)
18. Takeda K, Clausen BE, Kaisho T et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of STAT3 in macrophages and neutrophils. Immunity 10, 39-49 (1999). (Pubitemid 29077382)
19. Pardoll DM. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807-839 (2003).
20. Wang T, Niu G, Kortylewski M et al. Regulation of the innate and adaptive immune responses by STAT3 signaling in tumor cells. Nature Med. 10, 48-54 (2004). (Pubitemid 38524698)
21. Cheng F, Wang HW, Cuenca A et al. Critical role for STAT3 signaling in immune tolerance. Immunity 19, 425-436 (2003). (Pubitemid 37153418)
22. Grandis JR, Drenning SD, Zeng Q et al. Constitutive activation of STAT3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proc. Natl Acad. Sci. 97, 4227-4232 (2000). (Pubitemid 30226115)
23. Niu G, Bowman T, Huang M et al. Roles of activated Src and STAT3 signaling in melanoma tumor cell growth. Oncogene 21, 7001-7010 (2002). (Pubitemid 35252974)
24. Catlett-Falcone R, Landowski TH, Oshiro MM et al. Constitutive activation of STAT3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10, 105-115 (1999). (Pubitemid 29077388)
25. Epling-Burnette PK, Liu JH, Catlett- Falcone R et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J. Clin. Invest. 107, 351-362 (2001).
26. Aoki Y, Feldman GM, Tosato G. Inhibition of STAT3 signaling induces apoptosis and decreases survivin expression in primary effusion lymphoma. Blood 101, 1535-1542 (2003). (Pubitemid 36182531)
27. Shen Y, Devgan G, Darnell JE Jr, Bromberg JF. Constitutively activated STAT3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated STAT1. Proc. Natl Acad. Sci. 98, 1543-1548 (2001). (Pubitemid 32165535)
28. Prendergast GC. Mechanisms of apoptosis by c-Myc. Oncogene 18, 2967-2987 (1999). (Pubitemid 29276537)
29. Bowman T, Broome MA, Sinibaldi D et al. STAT3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl Acad. Sci. 98, 7319-7324 (2001). (Pubitemid 32567946)
30. Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res. 8, 945-954 (2002). (Pubitemid 35177340)
31. Kijima T, Niwa H, Steinman RA et al. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth Differ. 13, 355-362 (2002).
32. Masuda M, Suzui M, Yasumatu R et al. Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma. Cancer Res. 62, 3351-3355 (2002). (Pubitemid 34651376)
33. Sinibaldi D, Wharton W, Turkson J, Bowman T, Pledger WJ, Jove R. Induction of p21WAF1/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling. Oncogene 19, 5419-5427 (2000). (Pubitemid 32000908)
34. Vogelstein B, Lane D, Levine AJ. The p53 tumor-suppressor gene integrates numerous signals that control cell life and death. As when a highly connected node in the Internet breaks down, the disruption of p53 has severe consequences. Nature 408, 307-310 (2000).
35. Mora LB, Buettner R, Seigne J et al. Constitutive activation of STAT3 in human prostate tumors and cell lines direct inhibition of STAT3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 62, 6659-6666 (2002). (Pubitemid 35364135)
36. Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 19, 2474-2488 (2000). (Pubitemid 30339203)
37. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b, via PTEN and CYLD, are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 39, 493-506 (2010).
38. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 100, 57-70 (2000). (Pubitemid 30046295)
39. Rak J, Yu JL, Klement G, Kerbel RS. Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J. Invest. Derm. 5, 24-33 (2000). (Pubitemid 32044086)
40. Grunstein J, Roberts WG, Mathieu- Costello O, Hanahan D, Johnson RS. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res. 59, 1592-1598 (1999). (Pubitemid 29160131)
41. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 60, 203-212 (2000). (Pubitemid 30070735)
42. Niu G, Wright KL, Huang M et al. Constitutive STAT3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21, 2000-2008 (2002). (Pubitemid 34270888)
43. Wei D, Le X, Zheng L et al. STAT3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22, 319-329 (2003). (Pubitemid 36194328)
44. Li WC, Ye SL, Sun RX et al. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin. Cancer Res. 12, 7140-7148 (2006).
45. Niu G, Heller R, Catlett-Falcone R et al. Gene therapy with dominant-negative STAT3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res. 59, 5059-5063 (1999). (Pubitemid 29503958)
46. Bromberg JF, Wrzeszczynska MH, Devgan G et al. STAT3 as an oncogene. Cell 98, 295-303 (1999). (Pubitemid 29380565)
47. Siddiquee KAZ, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 18(2), 254-267 (2008). (Pubitemid 351206162)
48. Turkson J, Jove R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19(56), 6613-6626 (2000). (Pubitemid 32197700)
49. Niu G, Shain K, Huang M et al. Overexpression of a dominant-negative signal transducer and activator of transcription 3 variant in tumor cells leads to production of soluble factors that induce apoptosis and cell cycle arrest. Cancer Res. 61, 3276-3280 (2001). (Pubitemid 32695012)
50. Turkson J, Ryan D, Kim JS et al. Phosphotyrosyl peptides block STAT3- mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 276, 45443-45455 (2001).
51. Levy DE, Darnell JE Jr. STATs: transcriptional control and biological impact. Nature Rev. 3, 651-662 (2002).
52. Akira S. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene 19, 2607-2611 (2000). (Pubitemid 30339216)
53. Turkson J, Zhang S, Palmer J et al. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent anti-tumor activity. Mol. Cancer Ther. 3, 1533-1542 (2004). (Pubitemid 40136708)
54. Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM. Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/ signal transducer and activator of transcription 3 signaling pathway inhibitor with potent anti-tumor activity against human and murine cancer cells in mice. Cancer Res. 63, 1270-1279 (2003). (Pubitemid 36348705)
55. Kortylewski M, Kujawski M, Wang T et al. Inhibiting STAT3 signaling in the hematopoietic system elicits multicomponent anti-tumor immunity. Nat. Med. 11, 1314-1321 (2005). (Pubitemid 41752912)
56. Catlett-Falcone R, Dalton W, Jove R. STAT proteins as novel target for cancer theraphy. Curr. Opin. Oncol. 11(6), 490-496 (1999). (Pubitemid 29515894)
57. Costantino L, Barlocco D. STAT 3 as a target for cancer drug discovery. Curr. Med. Chem. 15, 834-843 (2008). (Pubitemid 351736406)
58. Yue P, Turkson J. Targeting STAT3 in cancer: how successful are we? Expert Opin. Invest. Drugs 18(1), 45-56 (2009).
59. Becker S, Groner B, M?ller CW. Three-dimensional structure of the STAT3b homodimer bound to DNA. Nature 394, 145-151 (1998). (Pubitemid 28325960)
60. Fletcher S, Turkson J, Gunning PT. Molecular approches towards the inhibition of the signal transducers and activator of transcription 3 (STAT3) protein. ChemMedChem 8, 1159-1168 (2008).
61. Ren Z, Cabell LA, Schaefer TS, McMurray JS. Identification of a high-affinity phosphopeptide inhibitor of STAT3. Bioorg. Med. Chem. Lett. 13, 633-636 (2003). (Pubitemid 36298456)
62. Timofeeva OA, Gaponenko V, Lockett SJ et al. Rationally designed inhibitors identify STAT3 N-domain as a promising anticancer drug target. ACS Chem. Biol. 2(12), 799-809 (2007). (Pubitemid 351166055)
63. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membrane. J. Biol. Chem. 269, 10444-10450 (1994). (Pubitemid 24198241)
64. Borghouts C, Kunz C, Delis N, Groner D. Monomeric recombinant peptide aptamers are required for efficient intracellular uptake and target inhibition. Mol. Cancer Res. 6(2), 267-281 (2008). (Pubitemid 351342415)
65. Dourlat J, Liu WQ, Sancier F et al. A novel nonphosphorylated potential anti-tumoral peptide inhibits STAT3 biological activity. Biochimie 91, 996-1002 (2009).
66. Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE. Interferon activation of the transcription factor STAT91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell 76(5), 821-828 (1994). (Pubitemid 24085320)
67. Vultur A, Cao J, Arulanandam R et al. Cell-to-cell adhesion modulates STAT3 activity in normal and breast carcinoma cells. Oncogene 2315, 2600-2616 (2004). (Pubitemid 38586314)
68. Ren Z, Coleman DR, Mandal PK et al. Peptidomimetic inhibitors of STAT3: structure-activity relationships and cellular activity. Presented at: The 16th EORTC-NCI-AACR, Symposium on Molecular Targets and Cancer Therapeutics. Genève, Switzerland, 28 September-1 October 2004.
69. Shuai K. Regulation of cytokine signaling pathways by PIAS proteins. Cell Res. 16, 196-202 (2006). (Pubitemid 43247977)
70. Borghouts C, Tittmann H, Delis N, Kirchenbauer M, Brill B, Groner B. The intracellular delivery of a recombinant peptide derived from the acidic domain of PIAS3 inhibits STAT3 transactivation and induces tumor cell death. Mol. Cancer Res. 8(4), 539-553 (2010).
71. Turkson J, Kim JS, Zhang S et al. Novel peptidomimetic inhibitors of signal transducers and activator of transcription 3 dimerization and biological activity. Mol. Cancer Ther. 3, 261-269 (2004). (Pubitemid 39193701)
72. Gunning PT, Katt WP, Glenn M et al. Isoform selective inhibition of STAT1 or STAT3 homo-dimerization via peptidomimetic probes: structural recognition of STAT SH2 domains. Bioorg. Med. Chem. Lett. 17, 1875-1878 (2007). (Pubitemid 46367686)
73. McMurray JS. Structural basis for the binding of high affinity phosphopeptides to STAT3. Biopolymers Peptide 90(1), 69-79 (2007).
74. Schust J, Berg T. A high-throughput fluorescence polarization assay for signal transducers and activator of transcription 3. Anal. Biochem. 330, 114-118 (2004). (Pubitemid 38746981)
75. Mandal PK, Heard PA, Ren Z, Chen X, McMurray JS. Solid-phase synthesis of STAT3 inhibitors incorporating O-carbamoylserine and O-carbamoylthreonine as glutamine mimics. Bioorg. Med. Chem. Lett. 17, 654-656 (2007). (Pubitemid 46108571)
76. Mandal PK, Ren Z, Chen X, Xiong C, McMurray JS. Structure-affinity relationships of glutamine mimics incorporated into phosphopeptides targeted to the SH2 domain of signal transducer and activator of transcription 3. J. Med. Chem. 52, 6126-6141 (2009).
77. Coleman DR, Kaluarachichi K, Ren Z, Chen X, McMurray JS. Solid-phase synthesis of phosphopeptides incorporating 2,2-dimethyloxazolidine pseudoproline analogues: evidence for trans Leu-Pro peptide bonds in STAT3 inhibitors. Int. J. Pept. Res. Ther. 14(1), 1-9 (2008). (Pubitemid 351321665)
78. Chen J, Nikolovska-Coleska Z, Yang CY et al. Design and synthesis of a new, conformationally constrained, macrocyclic small-molecule inhibitor of STAT3 via click chemistry. Bioorg. Med. Chem. Lett. 17, 3939-3942 (2007). (Pubitemid 46920935)
79. Dourlat J, Valentin B, Liu WQ, Garbay C. New synthesis of tetrazolylmethylphenylalanine and O-malonyltyrosine as pTyr mimetics for the design of STAT3 dimerization inhibitors. Bioorg. Med. Chem. Lett. 17, 3943-3946 (2007). (Pubitemid 46920946)
80. Gomez C, Bai L, Zhang J et al. Design, synthesis, and evalutation of peptidomimetics containing Freidinger lactams as STAT3 inhibitors. Bioorg. Med. Chem. Lett. 19, 1733-1736 (2009).
81. Coleman DR, Ren Z, Mandal PK et al. Investigation of the binding determinants of phosphopeptides targeted to the SRC homology 2 domain of the signal transducer and activator of transcription 3. Development of a high-affinity peptide inhibitor. J. Med. Chem. 48, 6661-6670 (2005). (Pubitemid 41504722)
82. Mandal PK, Liao WSL, McMurray JS. Synthesis of phosphatase-stable, cell-permeable peptidomimetic prodrugs that target the SH2 domain of STAT3. Org. Lett. 11(15), 3394-3397 (2009).
83. Chen J, Bai L, Bernard D et al. Structure-based design of conformationally constrained, cell-permeable STAT3 inhibitors. ACS Med. Chem. Lett. 1(2), 85-89 (2010).
84. Weidler M, Rether J, Anke T, Erkel G. Inhibition of interleukin-6 signaling by galiellalactone. FEBS Lett. 484, 1-6 (2000).
85. Shin DS, Kim HN, Shin KD et al. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 69(1), 193-202 (2009).
86. Siddiquee K, Gunning PT, Glenn M et al. An oxazole-based small-molecule STAT3 inhibitor modulates STAT3 stability and processing and induces anti-tumor cell effects. ACS Chem. Biol. 2(12), 787-798 (2007). (Pubitemid 351166054)
87. Fletcher S, Singh J, Zhang X et al. Disruption of transcriptionally active STAT3 dimers with nonphosphorylated, salicylic acid-based small molecules: potent in vitro and tumor cell activities. ChemBioChem 10(12), 1959-1964 (2009).
88. Gunning PT, Glenn MP, Siddiquee K et al. Targeting protein-protein interactions: suppression of STAT3 dimerization with rationally designed small-molecule, nonpeptidic SH2 domain binders. Chem. Bio. Chem. 9(17), 2800-2803 (2008).
89. Ge J, Wu H, Yao SQ. An unnatural amino acid that mimics phosphotyrosine. Chem. Commun. (Camb.) 46(17), 2980-2982 (2010).
90. Siddiquee K, Zhang S, Guida WC et al. Selective chemical probe inhibitor of STAT3, identified through structure-based virtual screening, induces anti-tumor activity. Proc. Natl Acad. Sci. USA 104(18), 7391-7396 (2007). (Pubitemid 47185916)
91. Zhang X, Yue P, Fletcher S, Zhao W, Gunning PT, Turkson J. A novel small-molecule disrupts STAT3 SH2 domain- phosphotyrosine interactions and STAT3- dependent tumor processes. Biochem. Pharmacol. 79(10), 1398-1409 (2010).
92. Song H, Wang R, Wang S, Lin J. A low-molecular-weight compound discovered through virtual database screening inhibits STAT3 function in breast cancer cells. Proc. Natl Acad. Sci. USA 102(13), 4700-4705 (2005). (Pubitemid 40471517)
93. Fuh B. Sobo M, Cen L et al. LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model. Br. J. Cancer 100(1), 106-112 (2009).
94. Bhasin D, Cisek K, Pandharkar T et al. Design, synthesis, and studies of small molecule STAT3 inhibitors. Bioor. Med. Chem. Lett. 18(1), 391-395 (2008).
95. Lin L, Brian H, Pui-Kai L et al. A novel small molecule, LLL12 inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia 12(1), 39-50 (2010).
96. Cui JR, Jian YJ, Wu YK, Wang SM. Synthesis of potential inhibitors for STAT-3 dimerization. Chinese J. Chem. 24, 1163-1169 (2006).
97. Uehara Y, Mochizuki M, Matsuno K, Haino T, Asai A. Novel high-throughput screening system for identifying STAT3-SH2 antagonists. Biochem. Biophys. Res. Comm. 380(3), 627-631 (2009).
98. Hao W, Hu Y, Niu C et al. Discovery of catechol structural moiety as a STAT3 SH2 domain inhibitor by virtual screening. Bioorg. Chem. Lett. 18, 4988-4992 (2008).
99. Shahani VM, Yue P, Haftchenary S et al. Identification of purine-scaffold small-molecule inhibitors of STAT3 activation by QSAR studies. ACS Med. Chem. Lett. 2(1), 79-84 (2011).
100. Turkson J, Zhang S, Palmer J et al. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent anti-tumor activity. Mol. Cancer Ther. 3(12), 1533-1542 (2004). (Pubitemid 40136708)
101. Turkson J, Zhang S, Mora LB et al. A novel platinum compound inhibits constitutive STAT3 signaling and induces cell cycle arrest and apoptosis of malignant cells. J. Biol. Chem. 280(38), 32979-32988 (2005). (Pubitemid 41368347)
102. Xu X, Kasembeli MM, Jiang X, Tweardy BJ, Tweardy DJ. Chemical probes that competitively and selectively inhibit STAT3 activation. PLoS One 4(3), e4783 (2009).
103. Matsuno K, Masuda Y, Uehara Y et al. Identification of a new series of STAT3 inhibitors by virtual screening. ACS Med. Chem. Lett. 1(8), 371-375 (2010).
104. Williamson JR. G-quartet structures in telomeric DNA. Annu. Rev. Biophys. Biomol. Struct. 23, 703-730 (1994).
105. Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S. Quadruplex DNA: sequence, topology and structure. Nucleic Acids Res. 34(19), 5402-5415 (2006). (Pubitemid 44742430)
106. Jing N, Zhu Q, Yuan P, Li Y, Mao L, Tweardy DJ. Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: a potential novel therapy for head and neck cancer. Mol. Cancer Ther. 5(2), 279-286 (2006).
107. Turkson J, Zhang S, Mora LB, Burns A, Sebti S, Jove R. A novel platinum compound inhibits constitutive STAT3 signaling and induces cell cycle arrest and apoptosis of malignant cells. J. Biol. Chem. 280(38), 32979-32988 (2005). (Pubitemid 41368347)
108. Weerasinghe P, Garcia GE, Zhu Q et al. Inhibition of STAT3 activation and tumor growth suppression of nonsmall cell lung cancer by G-quartet oligonucleotides. Int. J. Onc. 31, 129-136 (2007).
109. Leong PL, Andrews GA, Johnson DE et al. Targeted inhibition of STAT3 with a decoy oligonucleotide abrogates head and neck cancer cell growth. Proc. Natl Acad. Sci. USA 100, 4138-4143 (2003). (Pubitemid 36418170)
110. Barton BE, Murphy TF, Shu P, Huang HF, Meyenhofer M, Barton A. Novel single-stranded oligonucleotides that inhibit signal transducer and activator of transcription 3 induce apoptosis in vitro and in vivo in prostate cancer cell lines. Mol. Cancer Ther. 3, 1183-1191 (2004). (Pubitemid 39440162)
111. Hbibi T, Laguillier C, Souissi I et al. Efficient killing of SW480 colon carcinoma cells by a signal transducer and activator of transcription (STAT) 3 hairpin decoy oligodeoxynucleotide - interference with interferon-c-STAT1- mediated killing. FEBS J. 276, 2505-2515 (2009).
112. Zhanga X, Liua P, Zhang B, Wanga A, Yang M. Role of STAT3 decoy oligodeoxynucleotides on cell invasion and chemosensitivity in human epithelial ovarian cancer cells. Cancer Genet. Cytogen. 197, 46-53 (2010).
113. Masuda M, Suzui M, Weinstein B. Effect of epigallocatechin-3-gallate on growth, epidermal growyh factor receptor signalling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin. Cancer Res. 7, 4220-4229 (2001). (Pubitemid 34044648)
114. Way TD, Lee JC, Kuo DH et al. Inhibition of epidermal growth factor receptor signaling by Saussurea involucrata, a rare traditional Chinese medicinal herb, in human hormone-resistant prostate cancer PC-3 cells. J. Agric. Food Chem. 58(6), 3356-3365 (2010).
115. Zhou J, Ong C-N, Hur G-M, Shen H-M. Inhibition of the JAK-STAT3 pathway by andrographolide enhances chemosensitivity of cancer cells to doxorubicin. Biochem. Pharmacol. 79, 1242-1250 (2010).
116. Wesolowska O, Ku?d?al M, ?trancar T, Michalak K. Interaction of the chemopreventive agent resveratrol and its metabolite, piceatannol, with model membranes. Biochim. Biophys. Acta 1788, 1851-1860 (2009).
117. Su L, David M. Distinct mechanisms of STAT phosphorylation via the interferon-a/b receptor. Selective inhibition of STAT3 and STAT5 by piceatannol. J. Biol. Chem. 275, 12661-12666 (2000). (Pubitemid 30241415)
118. Sandra MLT, Li F, Rajendran P, Kumar AP, Hui KM, Sethi G. Identification of b-escin as a novel inhibitor of STAT3/JAK2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells. J. Pharmacol. Exp. Ther. 334, 285-293 (2010).
119. Wang YMX, Yan S, Shen S et al. 17-hydroxy-jolkinolide B inhibits signal transducers and activators of transcription 3 signaling by covalently cross-linking Janus kinases and induces apoptosis of human cancer cells. Cancer Res. 69(18), 7302-7310 (2009).
120. Sandur SK, Pandey MK, Sung B, Aggarwal BB. 5-hydroxy-2-methyl-1,4- naphthoquinone, a vitamin K3 analogue, suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase, SHP-1: potential role in chemosensitization. Mol. Cancer Res. 8(1), 107-118 (2010).
121. Ito S, Oyake T, Murai K, Ishida Y. Deguelin suppresses cell proliferation via the inhibition of survivin expression and STAT3 phosphorylation in HTLV-1-transformed T cells. Leukemia Res. 34(3), 352-357 (2010).
122. Dixit D, Sharma V, Ghosh S, Koul N, Mishra PK, Sen E. Manumycin inhibits STAT3, telomerase activity, and growth of glioma cells by elevating intracellular reactive oxygen species generation. Free Radic. Biol. Med. 47, 364-374 (2009).
123. Zhang J, Li L, Kim SH, Hagerman AE, Lu J. Anticancer, antidiabetic and other pharmacologic and biological activities of penta-galloyl-glucose. Pharm. Res. 26(9), 2066-2080 (2009).
124. Hu H, Lee HJ, Jiang C et al. Penta-1,2,3,4,6- O-galloyl-B-d-glucose induces p53 and inhibits STAT3 in prostate cancer cells in vitro and suppresses prostate xenograft tumor growth in vivo. Mol. Cancer Ther. 7(9), 2681-2691 (2008).
125. Agarwal C, Tyagi A, Kaur M, Agarwal R. Silibinin inhibits constitutive activation of STAT3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. Carcinogenesis 28, 1463-1470 (2007). (Pubitemid 47243538)
126. Sobota R, Szwed M, Kasza A, Bugno M, Kordula T. Parthenolide inhibits activation of signal transducers and activators of trascription (STATs) induced by cytokines of the IL-6 family. Biochem. Biophys. Res. Commun. 267, 329-333 (2000). (Pubitemid 30072551)
127. Del Bano MJ, Lorente J, Castillo J et al. Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development of leaves, flowers, stems, and roots of Rosmarinus officinalis. Antioxidant activity. J. Agric. Food Chem. 51, 4247-4253 (2003).
128. Lai CS, Lee HJ, Ho CT et al. Rosmanol potently inhibits lipopolysaccharide-induced iNOS and COX-2 expression through downregulating MAPK, NF-KB, STAT3 and C/EBP signaling pathways. J. Agric. Food Chem. 57, 10990-10998 (2009).
129. Zhang C, Li B, Gaikwad AS et al. Avicin D selectively induces apoptosis and downregulates p-STAT-3, Bcl-2, and survivin incutaneous T-cell lymphoma cells. J. Invest. Derm. 128, 2728-2735 (2008).
130. Wang Z, Jin H, Xu R, Mei Q, Fan D. Triptolide downregulates Rac1 and the JAK/ STAT3 pathway and inhibits colitis-related colon cancer progression. Exp. Mol. Med. 41(10), 717-727 (2009).
131. Lin L, Hutzen B. Zuo M et al. Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res. 70(6), 2445-2454 (2010).
132. Kim BH, Oh SR, Yin CH et al. MS-1020 is a novel small molecule that selectively inhibits JAK3 activity. Br. J. Haematol. 148, 132-143 (2009).
133. Kim BH, Yin CH, Guo Q et al. A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells. Mol. Cancer Ther. 7(9), 2672-2680 (2008).
134. Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2-selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia 22(9), 1790-1792 (2008).
135. Cotto M, Cabanillas F, Tirado M, Garcia MV, Pacheco E. Epigenetic therapy of lymphoma using histone deacetylase inhibitors. Clin. Transl. Oncol. 12(6), 401-409 (2010).
136. Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology 1, 636-642 (2009).
137. Lin KL, Su JC, Chien CM et al. Naphtho[1,2-b]furan-4,5-dione disrupts Janus kinase-2 and induces apoptosis in breast cancer MDA-MB-231. Toxicol. In Vitro 24(4), 1158-1167 (2010).
138. Hedvat M, Huszar D, Herrmann A et al. The JAK2 inhibitor AZD1480 potently blocks STAT3 signaling and oncogenesis in solid tumors. Cancer Cell 16(6), 487-497 (2009).
139. Scuto A, Krejci P, Popplewell L et al. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia DOI: 10.1038/ leu.2010.289 (2010) (Epub ahead of print).
140. Ioannidis S, Lamb ML, Wang T et al. Discovery of 5-chloro-N2-[(1S)-1-(5- fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl- 1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/ STAT pathway. J. Med Chem. 54(1), 262-276 (2011).
141. Verstovsek S, Kantarjian H, Mesa RA et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 363(12), 1117-1127 (2010).
142. Mesa RA. Ruxolitinib, a selective JAK1 and JAK2 inhibitor for the treatment of myeloproliferative neoplasms and psoriasis. Drugs 13(6), 394-403 (2010).
143. Campas-Moya C. Ruxolitinib: tyrosine-protein kinase JAK2 inhibitor: treatment of myelofibrosis: treatment of myeloproliferative neoplasms: treatment pf psoriasis. Drugs Fut. 35(6), 457-465 (2010).
144. Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A. CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia 23(8), 1441-1445 (2009).
145. Burns CJ, Bourke DG, Andrau L et al. Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs). Bioorg. Med. Chem. Lett. 19(20), 5887-5892 (2009).
146. Pedranzini L, Dechow T, Berishaj M et al. Pyridone 6, a pan-Janus-activated kinase inhibitor, induces growth inhibition of multiple myeloma cells. Cancer Res. 66(19), 9714-9721 (2006). (Pubitemid 44623672)
147. Quint?s-Cardama A, Manshouri T, Estrov Z et al. Preclinical characterization of atiprimod, a novel JAK2 and JAK3 inhibitor. Invest. New Drugs DOI: 10.1007/s10637-010- 9429-z (2010). (Epub ahead of print).
148. Vazina MA, Shishodia D, Harris D et al. Atiprimod blocks STAT3 phosphorilation and induces apoptosis in multiple myeloma cells. Br. J. Cancer 93, 70-80 (2005). (Pubitemid 41076255)
149. Ramakrishnan V, Timm M, Haug JL et al. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant antimyeloma activity and synergizes with common antimyeloma drugs. Oncogene 29(8), 1190-1202 (2010).
150. Yang F, Brown C, Buettner R et al. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3. Mol. Cancer Ther. 9(4), 953-962 (2010).
151. Sen B, Saigal B, Parikh N, Gallik G, Johnson FM. Sustained Src inhibition results in signal transducer and activator of transcription 3 (STAT3) activation and cancer cell survival via altered Janus-activated kinase-STAT3 binding. Cancer Res. 69(5), 1958-1965 (2009).
152. Averett Byers L, Sen B, Saigal B et al. Reciprocal regulation of c-Srg and STAT3 in nonsmall cell lung cancer. Clin. Cancer Res. 12(22), 6852-6861 (2009).
153. Premkumar DR, Jane EP, Agostino NR, Scialabbar JL, Pollack IF. Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. J. Carcinog. 9(7), 1-14 (2010).
154. Hutzen B, Friedman L, Sobo M et al. Curcumin analogue GO-Y030 inhibits STAT3 activity and cell growth in breast and pancreatic carcinomas. Int. J. Oncol. 35(4), 867-872 (2009).
155. Keinosuke R, Michiro S, Edwin C et al. Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of STAT3 pathway. BMC Cancer 10, 187-197 (2010).
156. Dowlati A, Kluge A, Nethery D, Halmos B, Kern J. SCH66336, inhibitor of protein farnesylation, blocks signal transducer and activators of transcription 3 signaling in lung cancer and interacts with a small molecule inhibitor of epidermal growth factor receptor/ human epidermal growth factor receptor 2. AntiCancer Drugs 19(1), 9-16 (2008). (Pubitemid 350190963)
157. Venkatasubbarao K, Choudary A, Freeman JW. Farnesyl transferase inhibitor (R115777)-induced inhibition of STAT3 (Tyr705) phosphorylation in human pancreatic cancer cell lines require extracellular signal-regulated kinases. Cancer Res. 65(7), 2861-2871 (2005). (Pubitemid 40490090)
158. Horiguchi A, Asano T, Kuroda K et al. STAT3 inhibitor WP1066 as a novel therapeutic agent for renal cell carcinoma. Br. J. Cancer 102(11), 1592-1599 (2010).
159. Ren X, Duan L, He Q et al. Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway. ACS Med. Chem. Lett. 1(9), 454-459 (2010).
160. Bhargava A, Vaishampayan UN. Satraplatin: leading the new generation of oral platinum agents. Expert Opin. Investig. Drugs 18(11), 1787-1797 (2009).
161. Gariboldi MB, Ravizza R, Molteni R, Osella D, Gabano E, Monti E. Inhibition of STAT3 increases doxorubicin sensitivity in human metastatic breast cancer cell line. Cancer Lett. 258, 181-188 (2007). (Pubitemid 350101017)
162. Ngan CY, Yamamoto H, Takagi A et al. Oxaliplatin induces mitotic catastrophe and apoptosis in esophageal cancer cells. Cancer Sci. 99(1), 129-139 (2008). (Pubitemid 350239041)
163. Shin D-S, Masciocchi D, Gelain A et al. Synthesis, modeling, and crystallographic study of 3,4-disubstituted-1,2,5-oxadiazoles and evaluation of their ability to decrease STAT3 activity. Med. Chem. Comm. 1(2), 156-164 (2010).
164. Jougasaki M, Ichiki T, Takenoshita Y, Setoguchi M. Statins suppress interleukin-6- induced monocyte chemo-attractant protein-1 by inhibiting Janus kinase/signal transducers and activators of transcription pathways in human vascular endothelial cells. Br. J. Pharmacol. 159(6), 1294-1303 (2010).
165. Lee CS, Shin YJ, Won C et al. Simvastatin acts as an inhibitor of interferon g-induced cycloxygenase-2 expression in human THP-1 cells, but not in murine RAW264.7 cells. Biocell. 33(2), 107-114 (2009).
166. Jung JE, Kim HS, Lee CS et al. Caffeic acid and its synthetic derivative CADPE suppress tumor angiogenesis by blocking STAT3- mediated VEGF expression in human renal carcinoma cells. Carcinogenesis 28(8), 1780-1787 (2007). (Pubitemid 47289042)
167. Masahiro O, Naoko S, Masanobu S et al. 12-O-tetradecanoylphorbol-13- acetate inhibits melanoma growth by inactivation of STAT3 through protein kinase c-activated tyrosine phosphatase(s). J. Biol. Chem. 284(44), 30416-30423 (2009).
168. Yiin JJ, Hu B, Schornack PA et al. ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain. Mol. Cancer Ther. 9(4), 929-941 (2010).
169. Uckun FM, Dibirdik I, Qazi S, Yiv S. Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells. Arzneimittelforschung Journal 60(4), 210-217 (2010).
170. Gariboldi MB, Ravizza R, Monti E. The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells. Biochem. Pharmacol. 80(4), 455-462 (2010).
171. Yang Y, Takayuki I, Tamotsu T et al. HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling. Cancer Science 96(7), 425-433 (2005). (Pubitemid 41179744)
172. Nelson EA, Walker SR, Kepich A et al. Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3. Blood 112(13), 5095-5102 (2008).
173. Kim HW, Kim JL, Lee HK, Hur DY, Yun IH, Kim SD. Enalapril alters expression of key growth factors in experimental diabetic retinopathy. Curr. Eye Res. 34(11), 976-987 (2009).
174. Yu ZY, Huang R, Xiao H et al. Fluacrypyrim, a novel STAT3 activation inhibitor, induces cell cycle arrest and apoptosis in cancer cells harboring constitutively-active STAT3. Int. J. Cancer 127(6), 1259-1270 (2010).
175. Shao W, Growney JD, Feng Y et al. Activity of deacetylase inhibitor panobinostat (LBH589) in cutaneous T-cell lymphoma models: defining molecular mechanisms of resistance. Int. J. Cancer 127(9), 2199-2208 (2010).
176. Changyou L, Yan Z, Malabika S et al. Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death. Mol. Cancer Ther. 8(8), 2211-2220 (2009).
177. Korehito K, Nantiga V, Kayono H et al. A redox-silent analogue of tocotrienol acts as a potential cytotoxic agent against human mesothelioma cells. Life Sciences 84(19-20), 650-656 (2009).
178. Lau CK, Yang ZF, Lam SP et al. Inhibition of STAT3 activity by YC-1 enhances chemo-sensitivity in hepatocellular carcinoma. Cancer Biol. Ther. 6(12), 1900-1907 (2007).
179. Selvendiran K, Bratasz A, Tong L, Ignarro LJ, Kuppusamy P. NCX-4016, a nitro-derivative of aspirin, inhibits EGFR and STAT3 signaling and modulates Bcl-2 proteins in cisplatin-resistant human ovarian cancer cells and xenografts. Cell Cycle 7(1), 81-88 (2008).
180. Chatterjee PK, Al-Abed Y, Sherry B, Metz CN. Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation. Am. J. Physiol. Cell Physiol. 297(5), C1294-C1306 (2009).
181. Lee HS, Han J, Lee SH, Park JA, Kim KW. Meteorin promotes the formation of GFAP-positive glia via activation of the Jak-STAT3 pathway. J. Cell Sci. 123(11), 1959-1968 (2010).
182. Nakaya A, Sagawa M, Muto A, Uchida H, Ikeda Y, Kizaki M. The gold compound auranofin induces apoptosis of human multiple myeloma cells through both down-regulation of STAT3 and inhibition of NF-kB activity. Leuk. Res. 35(2), 243-249 (2010).
183. McCleese JK, Bear MD, Fossey SL et al. The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines. Int. J. Cancer 125(12), 2792-2801 (2009).
184. Government of the USA. WO 2008151037 (2008).
185. Orchid Research Laboratories Limited. WO 2007042912 (2007).
186. Baylor College Medicine. WO 2006069001 (2006).
187. University of Central Florida Research Foundation, Inc. WO 2010033685 (2010).
188. H. Lee Moffitt Cancer Center & Research Institute. WO 2007136858 (2007).
189. Farjo R. WO 2009042677 (2009).
190. Baylor College Medicine. WO 2009149192 (2009).
191. Pharma IP General Incorporate Association. WO 2010004761 (2010).
192. Univesity of South Florida. WO 2007US2827 (2007).
193. Supergen, Inc. WO 2010011349 (2010).
194. Orchid Research Laboratories Limited. WO 2007042912 (2007).
195. Orchid Research Laboratories Limited. WO 2009060282 (2009).
196. Boston Biomedical, Inc. WO 2009036059 (2009).
197. Otsuka Pharmaceutical Co, Ltd. WO 2009057811 (2009).
198. Board of Regents, the Univesity of Texas System. WO 2010005807 (2010).
199. Kwon BM. US 20080051442 (2008).