The IKK NF-κB system: a treasure trove for drug development (original) (raw)

• 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).
  CAS PubMed Google Scholar
• Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).
  CAS PubMed Google Scholar
• Rothwarf, D. M., Zandi, E., Natoli, G. & Karin, M. IKK-γ is an essential regulatory subunit of the IκB kinase complex. Nature 395, 297–300 (1998).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Dejardin, E. et al. The lymphotoxin-β receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17, 525–535 (2002).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Li, Z. W. 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).
  CAS PubMed PubMed Central Google Scholar
• 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). This paper demonstrates that the IKK-β ablation is a driving force for the initiation and maintenance of acute systemic inflammation.
  CAS PubMed Google Scholar
• Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase. Science 284, 316–320 (1999).
  CAS PubMed Google Scholar
• Hu, Y. et al. IKKα controls formation of the epidermis independently of NF-κB. Nature 410, 710–714 (2001).
  CAS PubMed Google Scholar
• Cao, Y. et al. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107, 763–775 (2001).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Israel, A. Signal transduction: a regulator branches out. Nature 423, 596–597 (2003).
  CAS PubMed Google Scholar
• Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).
  CAS PubMed Google Scholar
• Karin, M. & Lin, A. NF-κB at the crossroads of life and death. Nature Immunol. 3, 221–227 (2002).
  CAS Google Scholar
• Barnes, P. J. & Karin, M. Nuclear factor-κB — a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).
  CAS PubMed Google Scholar
• Neurath, M. F. et al. Cytokine gene transcription by NF-κB family members in patients with inflammatory bowel disease. Ann. NY Acad. Sci. 859, 149–159 (1998).
  CAS PubMed Google Scholar
• Luque, I. & Gelinas, C. Rel/NF-κB and IκB factors in oncogenesis. Semin. Cancer. Biol. 8, 103–111 (1997).
  CAS PubMed Google Scholar
• Gilmore, T. D., Koedood, M., Piffat, K. A. & White, D. W. Rel/NF-κB/IκB proteins and cancer. Oncogene 13, 1367–1378 (1996).
  CAS PubMed Google Scholar
• Haefner, B. NF-κB: arresting a major culprit in cancer. Drug Discov. Today 7, 653–663 (2002).
  CAS PubMed Google Scholar
• Alkalay, I. et al. Stimulation-dependent IκB-α phosphorylation marks the NF-κB inhibitor for degradation via the ubiquitin–proteasome pathway. Proc. Natl Acad. Sci. USA 92, 10599–10603 (1995).
  CAS PubMed PubMed Central Google Scholar
• Xiao, G. et al. Retroviral oncoprotein Tax induces processing of NF-κB2/p100 in T cells: evidence for the involvement of IKKα. EMBO J. 20, 6805–6815 (2001).
  CAS PubMed PubMed Central Google Scholar
• Lenz, H. J. Clinical update: proteasome inhibitors in solid tumors. Cancer Treat Rev. 29 (Suppl. 1), 41–48 (2003).
  CAS PubMed Google Scholar
• Kitagawa, M. et al. An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of β-catenin. EMBO J. 18, 2401–2410 (1999).
  CAS PubMed PubMed Central Google Scholar
• Winston, J. T. et al. The SCF-βTRCP ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBβ and B-catenin and stimulates IκBα ubiquitination in vitro. Genes Dev. 13, 270–283 (1999).
  CAS PubMed PubMed Central Google Scholar
• Fuchs, S. Y., Chen, A., Xiong, Y., Pan, Z. Q. & Ronai, Z. HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IκB and β-catenin. Oncogene 18, 2039–2046 (1999).
  CAS PubMed Google Scholar
• Rubinfeld, B. et al. Stabilization of β-catenin by genetic defects in melanoma cell lines. Science 275, 1790–1792 (1997).
  CAS PubMed Google Scholar
• Morin, P. J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).
  CAS PubMed Google Scholar
• Kopp, E. & Ghosh, S. Inhibition of NF-κB by sodium salicylate and aspirin. Science 265, 956–959 (1994).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Yin, M. -J., Yamamoto, Y. & Gaynor, R. B. The anti-inflammatory agents aspirin and salicylate inhibit the activity of IκB kinase-β. Nature 396, 77–80 (1998). This is the first study to provide evidence that IKK-β is a potential target for NF-κB inhibition.
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Berman, K. S. et al. Sulindac enhances tumor necrosis factor-α-mediated apoptosis of lung cancer cell lines by inhibition of nuclear factor-κB. Clin. Cancer Res. 8, 354–360 (2002).
  CAS PubMed Google Scholar
• Yasui, H., Adachi, M. & Imai, K. Combination of tumor necrosis factor-α with sulindac augments its apoptotic potential and suppresses tumor growth of human carcinoma cells in nude mice. Cancer 97, 1412–1420 (2003).
  CAS PubMed Google Scholar
• 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).
  Google Scholar
• Yan, F. & Polk, D. B. Aminosalicylic acid inhibits IκB kinase-α phosphorylation of IκBα in mouse intestinal epithelial cells. J. Biol. Chem. 274, 36631–36636 (1999).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Dredge, K., Dalgleish, A. G. & Marriott, J. B. Thalidomide analogs as emerging anti-cancer drugs. Anticancer Drugs 14, 331–335 (2003).
  CAS PubMed Google Scholar
• Keifer, J. A., Guttridge, D. C., Ashburner, B. P. & Baldwin, A. S. Jr. Inhibition of NF-κB activity by thalidomide through suppression of IκB kinase activity. J. Biol. Chem. 276, 22382–22387 (2001).
  CAS PubMed Google Scholar
• Majumdar, S., Lamothe, B. & Aggarwal, B. B. Thalidomide suppresses NF-κB activation induced by TNF and H2O2, but not that activated by ceramide, lipopolysaccharides, or phorbol ester. J. Immunol. 168, 2644–2651 (2002).
  CAS PubMed Google Scholar
• Mitsiades, N. et al. Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood 99, 4525–4530 (2002).
  CAS PubMed Google Scholar
• Gilroy, D. W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000).
  CAS PubMed Google Scholar
• Straus, D. S. et al. 15-deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc. Natl Acad. Sci. USA 97, 4844–4849 (2000).
  CAS PubMed PubMed Central Google Scholar
• Lawrence, T., Gilroy, D. W., Colville-Nash, P. R. & Willoughby, D. A. Possible new role for NF-κB in the resolution of inflammation. Nature Med. 7, 1291–1297 (2001).
  CAS PubMed Google Scholar
• Bowie, A. G. & O'Neill, L. A. Vitamin C inhibits NF-κB activation by TNF via the activation of p38 mitogen-activated protein kinase. J. Immunol. 165, 7180–7188 (2000).
  CAS PubMed Google Scholar
• Carcamo, J. M., Pedraza, A., Borquez-Ojeda, O. & Golde, D. W. Vitamin C suppresses TNFα-induced NF-κB activation by inhibiting IκBα phosphorylation. Biochemistry 41, 12995–13002 (2002).
  CAS PubMed Google Scholar
• Tsai, S. H., Liang, Y. C., Lin-Shiau, S. Y. & Lin, J. K. Suppression of TNFα-mediated NF-κB activity by myricetin and other flavonoids through downregulating the activity of IKK in ECV304 cells. J. Cell Biochem. 74, 606–615 (1999).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Berlett, B. S. & Stadtman, E. R. Protein oxidation in aging, disease, and oxidative stress. J. Biol. Chem. 272, 20313–20316 (1997).
  CAS PubMed Google Scholar
• Hayakawa, M. et al. Evidence that reactive oxygen species do not mediate NF-κB activation. EMBO J. 22, 3356–3366 (2003).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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 inflammation. J. Immunol. 157, 1630–1637 (1996).
  CAS PubMed Google Scholar
• Anest, V. et al. A nucleosomal function for IκB kinase-α in NF-κB-dependent gene expression. Nature 423, 659–663 (2003).
  CAS PubMed Google Scholar
• Signal Pharmaceuticals, Inc. Quinazoline analogs and related compounds and methods for treating inflammatory conditions. WO 199901441 (1999).
• Leisten, J. C. et al. Identification of a disease modifying IKK2 inhibitor in rat adjuvant arthritis. Inflamm. Res. 51 (Suppl. 2), A25 (2002).
  Google Scholar
• Palanki, M. S. et al. Structure–activity relationship studies of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: an inhibitor of AP-1 and NF-κB mediated gene expression. Bioorg. Med. Chem. Lett. 12, 2573–2577 (2002).
  CAS PubMed Google Scholar
• Aventis Pharma. Preparation of substituted β-carbolines as potential therapeutics in diseases associated with increased IκB kinase activity. WO 2001068648 (2001).
• Castro, A. C. et al. Novel IKK inhibitors: β-carbolines. Bioorg. Med. Chem. Lett. 13, 2419–2422 (2003).
  CAS PubMed Google Scholar
• Hideshima, T. et al. NF-κB as a therapeutic target in multiple myeloma. J. Biol. Chem. 277, 16639–16647 (2003). This paper reports the use of small-molecule inhibitors of IKK-β to prevent NF-κB activation, and its thrapeutic role in inhibiting the growth of the haematological cancer multiple myeloma.
  Google Scholar
• Bristol-Myers Squibb Co. Method of treating inflammatory and immune diseases using 4-amino substituted imidazoquinoxaline, benzopyrazoloquinazoline, benzoimidazoquinoxaline and benzoimidazoquinoline inhibitors of IκB kinase (IKK). WO 2002060386 (2002).
• 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. 278, 1450–1456 (2003).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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, 32861–32871 (2003). References 65 and 67 focus on the therapeutic potential of small-molecule inhibitors of IKK-β for the treatment of inflammation. The molecule in reference 65 is an allosteric site inhibitor of IKK-β, whereas reference 67 reports the development of an ATP-competitive inhibitor of IKK-β.
  CAS PubMed Google Scholar
• Smithkline Beecham Corp. Preparation of 2-aminothiophene-3-carboxamides as NF-κB inhibitors. WO 2002030353 (2002).
• SmithKline Beecham Corp. NF-κB inhibitors. WO 2003029242 (2003).
• AstraZeneca. Preparation of ureido–carboxamido thiophene as inhibitors of IKK2 kinase. WO 2003010163 (2003).
• AstraZeneca. Preparation of thiophenecarboxamides as inhibitors of the enzyme IKK-2. WO 2001058890 (2001).
• 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).
  Google Scholar
• Bayer. Preparation of 2,4-diarylpyridines as IκB kinase β inhibitors useful as antiinflammatories. WO 2002044153 (2002).
• Bayer, P paration of hydroxyarylpyridines with IκB kinase β (IKK) inhibiting activity. WO 2002024679 (2002).
• 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).
  CAS PubMed Google Scholar
• Signal Pharmaceuticals, Inc. Preparation of anilinopyrimidines as IKK inhibitors. WO 2002046171 (2002).
• Bayer. Preparation of optically active pyridooxazinones as antiinflammatory agents. WO 2003076447 (2003).
• Aventis Pharma. Preparation of amino acid indolecarboxamides as modulators of NFκB activity. WO 2001030774 (2001).
• Aventis Pharma. Preparation of benzimidazolecarboxylic acid amino acid amides as IκB kinase inhibitors. WO 2001000610 (2001).
• Pharmacia Corp. Preparation of pyrazolo [4,3-c]quinolines, chromeno [4,3-c] pyrazoles, and analogs for treatment of inflammation. WO 2003024936 (2003).
• Pharmacia Corp. Preparation of 4,5-dihydro-1H-benzo[g]indazole-3-carboxamides for treatment of inflammation. WO 2003024935 (2003).
• Tularik Inc. Preparation of imidazolylquinolinecarboxaldehyde semicarbazones as IKK modulators. WO 2002041843 (2002).
• Smithkline Beecham Corp. Preparation of 5-amino-1H-imidazole-4-carboxamides as NF-κB inhibitors. WO 200230423 (2002).
• Leo Pharma. A method using cyanoguanidine compounds for modulating NFκB activity and use for the treatment of cancer. WO 2002094265 (2002).
• Leo Pharma. Antitumor drug–cyanoguanidine IKK inhibitor combination. WO 2002094322 (2002).
• Schou, C. et al. Novel cyanoguanidines with potent oral antitumour activity. Bioorg. Med. Chem. Lett. 7, 3095–3100 (1997).
  CAS Google Scholar
• Hjarnaa, P. J. et al. CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo. Cancer Res. 59, 5751–5157 (1999).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Isis Pharmaceuticals, Inc. Antisense modulation of Inhibitor-κ B kinase-β gene expression WO 2000031105 (2000).
• Takaesu, G. et al. TAK1 is critical for IκB kinase-mediated activation of the NF-κB pathway. J. Mol. Biol. 326, 105–15 (2003). This study reports the first demonstration of RNAi-based gene silencing of the IKK proteins and further establishes the role of TAK1, IKK-α and IKK-β on TNF-α and IL-1 activation of the NF-κB pathway.
  CAS PubMed Google Scholar
• 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 TNFα-induced NF-κB activation but also reduce expression of E-selectin, an NF-κB-dependent target gene, in primary human endothelial cells. WO 2002156000 (2002).
• May, M. et al. Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex. Science 289, 1550–1554 (2000). This study reports on the identification of the NEMO binding domain (NMD) of IKK-β and the potential use of an NMD peptide to block activation of the NF-κB pathway.
  CAS PubMed Google Scholar