The IKK NF-κB system: A treasure trove for drug development

Nature Reviews Drug Discovery

Volumn 3, Issue 1, 2004, Pages 17-26

  Karin, Michael ^a   Yamamoto, Yumi ^b   Wang, Q May ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 (4 AMINO 1,3 DIHYDRO 1,3 DIOXO 2H ISOINDOL 2 YL)GLUTARIMIDE; ACETYLSALICYLIC ACID; AMIDE; BETA CARBOLINE DERIVATIVE; BMS 345541; FLAVANOID; GUANIDINE DERIVATIVE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDOMETACIN; LENALIDOMIDE; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; NONSTEROID ANTIINFLAMMATORY AGENT; PROSTAGLANDIN; PROSTAGLANDIN SYNTHASE; PYRIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; QUINAZOLINE DERIVATIVE; QUINOLINE DERIVATIVE; QUINOXALINE DERIVATIVE; RNA; SALAZOSULFAPYRIDINE; SALICYLIC ACID DERIVATIVE; SULINDAC; THALIDOMIDE; THALIDOMIDE DERIVATIVE; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA RECEPTOR; TUMOR NECROSIS FACTOR RECEPTOR; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTIINFLAMMATORY ACTIVITY; ANTINEOPLASTIC ACTIVITY; ARTHRITIS; AUTOIMMUNE DISEASE; CARCINOGENESIS; CLINICAL TRIAL; DOSE RESPONSE; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; GENE CONTROL; GENE DISRUPTION; HUMAN; INFLAMMATORY DISEASE; MULTIPLE MYELOMA; NONHUMAN; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION; UBIQUITINATION;

EID: 0346505340     PISSN: 14741776     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrd1279     Document Type: Review

References (92)

1. Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225-260 (1998).
2. Karin, M. & Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev. Immunol. 18, 621-663 (2000).
3. Solan, N. J., Miyoshi, H., Carmona, E. M., Bren, G. D. & Paya, C. V. RelB cellular regulation and transcriptional activity are regulated by p100. J Biol. Chem. 277, 1405-1418 (2002).
4. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81-S96 (2002).
5. Rothwarf, D. M., Zandi, E., Natoli, G. & Karin, M. IKK-γ is an essential rregulatory subunt of the IκB kinase complex. Nature 395, 297-300 (1998).
6. Makris, C. et al. Female mice heterozygous for IKK-γ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell. 5, 969-979 (2000).
7. Dejardin, E. et al. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525-535 (2002).
8. Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F. & Verma, I. M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321-325 (1999).
9. Li, Z. et al. The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839-1845 (1999).
10. Chen, L. W. et al. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nature Med. 9, 575-581 (2003).
11. Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking teh IKKα subunity of IκB kinase. Science 284, 316-320 (1999).
12. Hu, Y. et al. IKKα controls formation of the epidermis independently of NF-κB. Nature 410, 710-714 (2001).
13. Cao, Y. et al. IKKα provides an essential link between RANK signalling and cyclin D1 expression during mammary gland development. Cell 107, 763-775.
14. Yamamoto, Y., Verma, U. N., Prajapati, S., Kwak, Y. T. & Gaynor, R.B. Histone H3 phosphorylation by IKK-α is critical for cytokine-induced gene expression. Nature 423, 655-659 (2003).
15. Israel, A. Signal transduction: a regulator branches out. Nature 423, 596-597 (2003).
16. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signalling pathway. Science 293, 1495-1499 (2001).
17. Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nature Immunol. 3, 221-227 (2002).
18. Barnes, P. J. & Karin, M. Nuclear factor-κB - a povital transcription factor in chronic inflammatory disease. N. Engl. J. Med 336, 1066-1071 (1997).
19. Neurath, M. F. et al. Cytokine gene transcription by NF-κB family members in patients with imflammatory bowel disease. Ann. NY Acad. Sci. 859, 149-159 (1998).
20. Luque, I. & Gelinas, C. Rel/NF-κB and IκB factors in oncogenesis. Semin. Cancer. Biol. 8, 103-111 (1997).
21. Gilmore, T. D., Koedood, M., Piffat, K. A. & White, D. W. Rel/NF-κB/IκB proteins and cancer. Oncogene 13, 1367-1378 (1996).
22. Haefner, B. NF-κB: arresting a major culprit in cancer. Drug Discov. Today 7, 653-663 (2002).
23. Alkalay, I. et al. Stimulation-dependent IκB-α phosphorylation marks the NF-κB inhibitor for degradation via the ubiuitin-proteasome pathway. Proc, Natl Acad. Sci. USA 92, 10599-10603 (1995).
24. Xiao, G. et al. Retoviral oncoprotein Tax induces processing of NF-κB2/p00 in T cells: evidence for the involvement of IKKα. EMBO J. 20, 6805-6815 (2001).
25. Lenz, H. J. Clinical update: proteasome inhibitors in solid tumors. Cancer Treat Rev. 29 (Suppl. 1), 41-48 (2003).
26. Kitagawa, M. et al. An F-box protein, FWD1, mediates ubiquitib-dependent proteolysis of β-catenin. EMBO J. 18, 2401-2410 (1999).
27. Winston, J. T. et al. The SCF-βTRCP ubiquitib ligase complex associates specifically with pohosphorylated destruction motifs in IκBβ and B-cetanin and stimulates IκBα ubiquitination in vitro. Genes Dev. 13, 270-283 (1999).
28. Fuchs, S. Y., Chen, A., Xiong, Y., Pan, Z.Q. & Ronai, Z. HOS, a human homolog of Slimb, forms an SCF complex with Skp and Cullin 1 and targets the phosphorylation-dependent degradation of IκB and β-cetanin. Oncogene 18, 2039-2046 (1999).
29. Rubinfeld, B. et al. Stabilization of β-catenin by genetic defects in melanoma cell lines. Science 275, 1790-1792 (1997).
30. Morin, P. J. et al. Activation of β-cetanin -Tcf signalling in colon cancer by mutations in β-cetanin or APC. Science 275, 1787-1790 (1997).
31. Kopp, E. & Ghosh, S. Inhibition of NF-κB by sodium salicylates and aspirin. Science 265, 956-95 (1994).
32. Pierce, J. W., Read, M. A., Ding, H., Luscinskas, F. W. & Collins, T. Salicylates inhibit IκBα phosphorylation, endothelial-leukocyte adhesion molecule expression, and neutrophil transmigration. J. Immunol. 156, 3961-3969 (1996).
33. Yin, M.-Y., Yamamoto, Y. & Gaynor, R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77-80 (1998).
34. Yamamoto, Y., Yin, M.-J., Lin, K.-M. & Gaynor, R. B. Sulindac inhibits activation of the NF-κB pathway. J Biol. Chem. 274, 27307-27314 (1999).
35. Berman, K., et al. Sulindac enhance tumors necrosis factor-α-mediated apoptosis of lung cancer cell lines by inhibition of nuclear factor-κB. Clin Cancer Res. 8, 354-360 (2002 ).
36. Yasui, H., Adachi, M. & Imai K. Combination of tumor necrossis factor-α with sulindac augments its apoptotic potential and suppresses tumor growth of human carcinoma cells in nude mice. Cancer 97, 1412-1420 (2003).
37. Wahl, C., Liptay, S., Adler, G. & Schmid, R. M. Sulfasalazine: a potent and specific inhibitor of NF-κB. J Clin Invest. 101, 1163-1174 (1997).
38. Yan, F. & Polk, D. B. Aminosalicylic acid inhibitor IκB kinase-α phosphorylation of IκBα in mouse intestinal epithelial cells. J. Biol. Chem. 274, 36631-36636 (1999).
39. Egan, L. J. et al. Inhibition of interleukin-1-stimulated NF-κB RelA/p65 phosphorylation by mesalamine is accompanied by decreased transcriptional activity. J. Biol. Chem 274, 26448-26453 (1999 ).
40. Dredge, K., Dalgleish, A. G. & Marriott, J. B. Thalidomide analogs as emerging anti-cancer drugs. Anticancer Drugs 14, 331-335 (2003).
41. Kiefer, J. A., Guttridge, D. C., Ashburner, B. P. & Baldwin, A. S. Jr. Inhibitions of NF-κB activity by thalidomide through suppression of IκB kinase activity. J. Biol. Chem. 276, 22382-22387 (2001).
42. 2O2, but not that activated by ceramide, lipopolysaccharides, or phorb ester. J. Immunol. 168, 2644-2651 (2002).
43. Mitsiades, N. et al. Apoptic signalling induced by immunomodulatory thalidomide analogic in human multiple myeloma cells: therapeutic implications. Blood 99, 4525-4530 (2002).
44. Gilroy, D. W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nature Med. 5, 698-701 (1999).
45. Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J. & Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79-82 (1998).
46. Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103-108 (2000).
47. 12,14 prostaglandin J2 inhibits multiple steps in the NF-κB signalling pathway. Proc. Natl Acad. Sci. USA 97, 4844-4849 (2000).
48. Lawrence, T., Gilroy, D. W., Colville-Nash, P. R. & Willoughby, D. A. Possible new role for NF-κB in the resolution of inflammatory. Nature Med. 7, 1291-1297 (2001).
49. Bowie, A. G. & O'Neill, L. A. Vitamin C inhibits NF-κB activation by TNF via the activation of p38 milogen-activated protein kinase. J. Immunol. 165, 7180-7188 (2000).
50. Carcamo, J. M., Pedraza, A., Borquez-Ojeda, O. & Golde, D. W. Vitamin C suppresses TNFα-induced NF-κB activation by inbiting IκBα phosphorylation. Biochemistry 41, 12995-13002 (2002).
51. Tsai, S. H., Liang, Y. C., Lin-Shiau, S. Y. & Lin, J. K. Suppression of TNFα-mediated NF-κB activity by myricetin and other flovonoids through downregulating the activity of IKK in ECV304 cells. J. Cell Biochem. 74, 606-615 (1999).
52. Holmes-McNary, M. & Baldwin, A. S. Jr. Chemopreventive properties of trans-resveratrol are associated with inhibition of activation of the IκB kinase. Cancer Res. 60, 3477-3483 (2000).
53. Berlett, B. S. & Stadtman, E. R. Protein oxidation in aging, disease, and oxidatives stress. J Biol Chem. 272, 20313-20316 (1997).
54. Hayakawa, M. et al. Evidence that reactive oxygen species do not mediate NF-κB activation. EMBO J. 22, 3356-3366 (2003).
55. Sakon, S. et al. NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22, 3898-3909 (2003).
56. Blackwell, T. S., Blackwell, T. R., Holden, E. P., Christman, B. W. & Christman. J. W. In vivo antioxidant treatment suppresses nuclear factor-κB activation and neutrophilic lung inflammatory. J Immunol. 157, 1630-1637 (1996).
57. Anest, V. et al. A nucleosomal fucntion for IκB kinase-α in NF-κB-dependent gene expression. Nature 423, 659-663 (2003).
58. Signal Pharmaceuticals, Inc. Quinazoline analogs and related compounds and methods for treating inflammatory conditions. WO 199901441 (1999).
59. Leisten, J. C. et al. Identification of a disease modifying IKK2 inhibitor in adjuvant arthritis. Inflamm. Res. 51 (Suppl. 2), A25 (2002).
60. Palanki, M. S. et al. Structure-activity relationship studies of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4- (triflouromethyl)pyrimidine-5-carboxylate: an inhibitor of AP-1 and NF-κB mediated gene expression. Bioorg. Med Chem. Lett. 12, 2573-2577 (2002).
61. Aventis Pharma. Preparation of substitute β-carboline as potential therapeutics in disease associated with increased IκB kinase activity. WO 2001068648 (2001).
62. Castro, A. C. et al. Novell IKK inhibotors: β-carbolines. Bioorg. Med. Chem. Lett. 13, 2419-2422 (2003).
63. Hideshima, T. et al. NF-κB as a therapeutic target in multiple myeloma. J. Biol. Chem. 277, 16639-16647 (2003).
64. Bristol-Myers Squibb Co. Methods of treating inflammatory and immune disease using 4-amino substituted imidazoquinoxaline, benzopyrazoloquinazoline, benzoimidazquixaline and benzoimidazoquinoline inhibitors of IκB kinase (IKK). WO 2002060386 (2002).
65. Burke, J. R. et al. BMS-345541 is a highly selective inhibitor of IκB kinase that binds at an allosteric site of the enzyme and blocks NF-κB-dependent transcription in mice. J. Biol. Chem. 27, 1450-1456 (2003).
66. McIntyre, K. W. et al. A highly selective inhibitor of IκB kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. Arthritis Rheum. 48, 2652-2659 (2003).
67. Kishore, N. et al. A selective IKK-2 inhibitor blocks NF-κB-dependent gene expression in IL-1β stimulated synovial fibroblasts. J. Biol. Chem. 278, 32861-32861 (2003).
68. Smithkline Beecham Corp. Preparation of 2-amino-thiophene-3-carboxamides as NF-κB inhibitors. WO 2002030353 (2003).
69. SmithKline Beecham Corp. Preparation of NF-κB inhibitors. WO 2003029242 (2003).
70. AstraZeneca. Preparation of ureido-carboxamido thiophene as inhibitors of IKK2 kinase. WO 2003010163 (2003).
71. AstraZeneca. Preparation of thiophenecarboxamides as inhibitors of the enzyme IKK-2. WO 2001058890 (2001).
72. Roshak, A. K. et al. A small molecule inhibitor of IκB kinase β (IKKβ) blocks inflammation and protects joint integrity in in vivo models of arthritis. Inflamm. Res. 51 (Suppl. 2), S4 (2002).
73. Bayer. Preparation of 2,4-diarylpyridines as IκB kinase β inhibitors useful as antiinflammatories. WO 20020441563 (2002).
74. Bayer. Preparation of hydroxyarylpyridines with IκB kinase β (IKK) inhibiting activity. WO 2002024679 (2002).
75. Murata, T. et al. Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Part 1. Bioorg. Med. Chem. Lett. 13, 913-918 (2003).
76. Signal Pharmaceuticals, Inc. Preparation of anilinopyrimidines as IKK inhibitors. WO 2002046171 (2002).
77. Bayer. Preparation of optically active pyridooxaziones as antiinflammatory agents. WO 2003076447 (2003).
78. Aventis Pharma. Preparation of amino acid indolecarboxamides as modulators of NFκB activity. WO 2001030774 (2001).
79. Aventis Pharma. Preparation of benzimidazolecarboxylic acid amino acid amides as IκB kinase inhibitors. WO 2001000610 (2001).
80. Pharmacia Corp. Preparation of pyrazolo [4,3-c]quinolines, chromeno (4,3-c] pyrazoles, and analogs for treatment of inflammation. WO 2003024936 (2003).
81. Pharmacia Corp. Preparation of 4,5-dihydor-1H-benzo[g]indazole-3-carboxamides for treatment of inflammation. WO 2003024935 (2003).
82. Tularik Inc. Preparation of imidazolylquinolinecarbox-aldehyde semicarbazones as IKK modulators. WO 2002041843 (2002).
83. Smithkline Beecham Corp. Preparation of 5-amino-1H-imidazole-4-carboxamides as NF-κB inhibitors. WO 200230423 (2002).
84. Leo Pharma. A method using cyanoguanidine compounds for modulating NF-κB activity and use for the treatment of cancer. WO 2002094265 (2002).
85. Leo Pharma. Antitumor drug-cyanoguanidine IKK inhibitor combination. WO 2002094322 (2002).
86. Schou, C. et al. Novel cyanoguanidines with potent oral antitumor activity. Bioorg. Med. Chem. Lett. 7, 3095-3100 (1997).
87. Hjarnaa, P. J. et al. CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo. Cancer Res. 59, 5751-5757 (1999).
88. Martinsson, P. et al. The combination of the antitumoural pyridyl cyanoguanidine CHS 828 and etoposide in vitro - from cytotoxic synergy to complete inhibition of apoptosis. Br. J. Pharmacol. 137, 568-573, (2002).
89. Isis Pharmaceuticals, Inc. Antisense modulation of Inhibitor-κB kinase-β gene expression WO 2000031105 (2000).
90. Takaesu, G. et al. TAK1 is critical for IκB kinase-mediated activation of the NF-κB pathway. J. Mol. Biol. 326, 105-15 (2003).
91. May, M. J. & Ghosh, S. Anti-inflammatory compounds and uses thereof. A cell-permeable peptide encompassing NEMO binding domain of IκB kinase was able to not only inhibit TNT-α-induced NF-κB activation but also reduce expression of E-selctin, an NF-κB-dependent target gene, in primary human endothelial cells. WO 2002156000 (2002).
92. May, M. et al. Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO eith the IκB kinase complex. Science 289, 1550-1554 (2002).