Novel IκB kinase inhibitors for treatment of nuclear factor-κB-related diseases

Introduction: NF-κB is a key regulator of inflammation and immunity in cancer development. The IκB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -β and -γ. It is well known that many pro-inflammatory stimuli require the IKK-β subunit for NF-κB activation. Areas covered: NF-κB affects the progression of inflammation-related diseases, such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. Expert opinion: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.

[1]  S. Ghosh,et al.  Experimental Allergic Encephalomyelitis in the Adoptive Transfer Model of Essential Modifier-Binding Domain Peptides B k Antineuroinflammatory Effect of NF-Fung, , 2004 .

[2]  K. Ziegelbauer,et al.  Synthesis and structure–activity relationships of novel IKK-β inhibitors. Part 3: Orally active anti-inflammatory agents , 2004 .

[3]  A. Itai,et al.  Inhibition of IkappaB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury. , 2004, Cardiovascular research.

[4]  M. Karin,et al.  Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. , 2000, Annual review of immunology.

[5]  A. Smahi,et al.  Inherited disorders of NF-kappaB-mediated immunity in man. , 2004, Current opinion in immunology.

[6]  M. Karin,et al.  Missing Pieces in the NF-κB Puzzle , 2002, Cell.

[7]  J. Burke,et al.  Collagen and Aggrecan Degradation Is Blocked in Interleukin-1-Treated Cartilage Explants by an Inhibitor of IκB Kinase through Suppression of Metalloproteinase Expression , 2005, Journal of Pharmacology and Experimental Therapeutics.

[8]  J. Adams,et al.  Novel IKK inhibitors: beta-carbolines. , 2003, Bioorganic & Medicinal Chemistry Letters.

[9]  J. Adams,et al.  Novel IKK inhibitors: β-carbolines , 2003 .

[10]  K. McIntyre,et al.  A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collagen-induced arthritis in mice. , 2003, Arthritis and rheumatism.

[11]  L. Dang,et al.  Effects of IKK inhibitor PS1145 on NF-kappaB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells. , 2006, Oncogene.

[12]  Michael Karin,et al.  IKKβ Couples Hepatocyte Death to Cytokine-Driven Compensatory Proliferation that Promotes Chemical Hepatocarcinogenesis , 2005, Cell.

[13]  Matthew S. Hayden,et al.  New regulators of NF-κB in inflammation , 2008, Nature Reviews Immunology.

[14]  M. Karin,et al.  The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion , 2003, Nature Medicine.

[15]  R. Weichselbaum,et al.  Diverse TNFalpha-induced death pathways are enhanced by inhibition of NF-kappaB. , 2007, International journal of oncology.

[16]  R. Kurzrock,et al.  Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells. , 2006, Molecular cancer therapeutics.

[17]  T. Niki,et al.  A selective novel low‐molecular‐weight inhibitor of IκB kinase‐β (IKK‐β) prevents pulmonary inflammation and shows broad anti‐inflammatory activity , 2005 .

[18]  S. Bailey,et al.  Nuclear factor-kappaB activation: a molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer. , 2007, Molecular cancer therapeutics.

[19]  Y. Kaneda,et al.  Suppressed severity of collagen-induced arthritis by in vivo transfection of nuclear factor kappaB decoy oligodeoxynucleotides as a gene therapy. , 1999, Arthritis and rheumatism.

[20]  James R. Burke,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* , 2003, The Journal of Biological Chemistry.

[21]  J. Christman,et al.  Duration and Intensity of NF-κB Activity Determine the Severity of Endotoxin-Induced Acute Lung Injury1 , 2006, Journal of Immunology.

[22]  T. Niki,et al.  Discovery of novel and selective IKK-beta serine-threonine protein kinase inhibitors. Part 1. , 2003, Bioorganic & medicinal chemistry letters.

[23]  Y. Kaneda,et al.  Nuclear factor κB decoy oligodeoxynucleotides prevent endotoxin‐induced fatal liver failure in a murine model , 2003 .

[24]  A. Itai,et al.  Inhibition of NF-κB improves left ventricular remodeling and cardiac dysfunction after myocardial infarction , 2007 .

[25]  J. Falck,et al.  Overexpression of cytochrome P450 CYP2J2 protects against hypoxia-reoxygenation injury in cultured bovine aortic endothelial cells. , 2001, Molecular pharmacology.

[26]  A. Itai,et al.  A new IkappaB kinase beta inhibitor prevents human breast cancer progression through negative regulation of cell cycle transition. , 2006, Cancer research.

[27]  J. Schmid,et al.  BMS-345541 Targets Inhibitor of κB Kinase and Induces Apoptosis in Melanoma: Involvement of Nuclear Factor κB and Mitochondria Pathways , 2006, Clinical Cancer Research.

[28]  M. Bentires-Alj,et al.  Selective Blockade of NF-κB Activity in Airway Immune Cells Inhibits the Effector Phase of Experimental Asthma1 , 2004, Journal of Immunology.

[29]  Dong-Hyun Kim,et al.  A ginseng saponin metabolite suppresses tumor necrosis factor-α-promoted metastasis by suppressing nuclear factor-κB signaling in murine colon cancer cells , 2008 .

[30]  A. Itai,et al.  A novel NF-kappaB inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors. , 2005, Blood.

[31]  M. Caligiuri,et al.  Selective efficacy of depsipeptide in a xenograft model of Epstein-Barr virus-positive lymphoproliferative disorder. , 2004, Journal of the National Cancer Institute.

[32]  Capucine Picard,et al.  Inherited disorders of NF-κB-mediated immunity in man , 2004 .

[33]  S. Gerondakis,et al.  Genetic approaches in mice to understand Rel/NF-kappaB and IkappaB function: transgenics and knockouts. , 1999, Oncogene.

[34]  R. Kurzrock,et al.  Nuclear factor-κB maintains TRAIL resistance in human pancreatic cancer cells , 2006, Molecular Cancer Therapeutics.

[35]  A. Itai,et al.  A novel IkappaB kinase-beta inhibitor ameliorates bleomycin-induced pulmonary fibrosis in mice. , 2006, American journal of respiratory and critical care medicine.

[36]  M. Aoki,et al.  Prevention and regression of atopic dermatitis by ointment containing NF-kB decoy oligodeoxynucleotides in NC/Nga atopic mouse model , 2002, Gene Therapy.

[37]  M. Yao,et al.  A Selective IKK-2 Inhibitor Blocks NF-κB-dependent Gene Expression in Interleukin-1β-stimulated Synovial Fibroblasts* , 2003, Journal of Biological Chemistry.

[38]  Jen-kun Lin,et al.  Suppression of lipopolysaccharide-induced nuclear factor-κB activity by theaflavin-3,3′-digallate from black tea and other polyphenols through down-regulation of IκB kinase activity in macrophages , 2000 .

[39]  P. Barnes,et al.  Repression of Inflammatory Gene Expression in Human Pulmonary Epithelial Cells by Small-Molecule IκB Kinase Inhibitors , 2007, Journal of Pharmacology and Experimental Therapeutics.

[40]  Ruhang Tang,et al.  IKKbeta inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury. , 2007, American journal of physiology. Heart and circulatory physiology.

[41]  Dong-Hyun Kim,et al.  A ginseng saponin metabolite suppresses tumor necrosis factor-alpha-promoted metastasis by suppressing nuclear factor-kappaB signaling in murine colon cancer cells. , 2008, Oncology reports.

[42]  Michael Karin,et al.  NF-kappaB: linking inflammation and immunity to cancer development and progression. , 2005, Nature reviews. Immunology.

[43]  V. Imbert,et al.  NF‐κB inhibition triggers death of imatinib‐sensitive and imatinib‐resistant chronic myeloid leukemia cells including T315I Bcr‐Abl mutants , 2009, International journal of cancer.

[44]  Akiko Itai,et al.  Antiallergic and Anti-Inflammatory Effects of a Novel IκB Kinase β Inhibitor, IMD-0354, in a Mouse Model of Allergic Inflammation , 2008, International Archives of Allergy and Immunology.

[45]  A. Itai,et al.  Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction. , 2007, American journal of physiology. Heart and circulatory physiology.

[46]  M. Isobe,et al.  Tea catechins attenuate chronic ventricular remodeling after myocardial ischemia in rats. , 2007, Journal of molecular and cellular cardiology.

[47]  J. Schmid,et al.  BMS-345541 targets inhibitor of kappaB kinase and induces apoptosis in melanoma: involvement of nuclear factor kappaB and mitochondria pathways. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[48]  Simone Fulda,et al.  Sensitization of neuroblastoma cells for TRAIL‐induced apoptosis by NF‐κB inhibition , 2009, International journal of cancer.

[49]  J. F. Schindler,et al.  Novel Insights into the Cellular Mechanisms of the Anti-inflammatory Effects of NF-κB Essential Modulator Binding Domain Peptides , 2010, The Journal of Biological Chemistry.

[50]  Fajun Yang,et al.  The Green Tea Polyphenol (−)-Epigallocatechin-3-Gallate Blocks Nuclear Factor-κB Activation by Inhibiting IκB Kinase Activity in the Intestinal Epithelial Cell Line IEC-6 , 2001 .

[51]  A. Itai,et al.  Effect of nuclear factor-kappaB inhibition on rheumatoid fibroblast-like synoviocytes and collagen induced arthritis. , 2005, The Journal of rheumatology.

[52]  S. Ghosh,et al.  Selective inhibition of NF-κB activation by a peptide that blocks the interaction of NEMO with the IκB kinase complex , 2000 .

[53]  L. Staudt,et al.  Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[54]  M. Isobe,et al.  Dietary consumption of green tea catechins attenuate hyperlipidaemia-induced atherosclerosis and systemic organ damage in mice , 2005, Acta cardiologica.

[55]  K. McIntyre,et al.  A HIGHLY SELECTIVE INHIBITOR OF IκB KINASE, BMS-345541, AUGMENTS GRAFT SURVIVAL MEDIATED BY SUBOPTIMAL IMMUNOSUPPRESSION IN A MURINE MODEL OF CARDIAC GRAFT REJECTION , 2004, Transplantation.

[56]  Hong-Jin Kim,et al.  Active roles for inhibitory κB kinases α and β in nuclear factor-κB–mediated chemoresistance to doxorubicin , 2008, Molecular Cancer Therapeutics.

[57]  E. Campo,et al.  Selective Inhibition of IκB Kinase Sensitizes Mantle Cell Lymphoma B Cells to TRAIL by Decreasing Cellular FLIP Level1 , 2007, The Journal of Immunology.

[58]  Yukio Nakamura,et al.  Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts , 1999, Oncogene.

[59]  S. Horvath,et al.  Prostate Stem Cell Antigen Is Overexpressed in Prostate Cancer Metastases , 2005, Clinical Cancer Research.

[60]  M. Isobe,et al.  Tea catechins attenuate ventricular remodeling and graft arterial diseases in murine cardiac allografts. , 2006, Cardiovascular research.

[61]  R. Plevin,et al.  Selective inhibition of inhibitory kappa B kinase‐β abrogates induction of nitric oxide synthase in lipopolysaccharide‐stimulated rat aortic smooth muscle cells , 2005, British journal of pharmacology.

[62]  N. Munshi,et al.  NF-κB as a Therapeutic Target in Multiple Myeloma* , 2002, The Journal of Biological Chemistry.

[63]  A. Itai,et al.  A novel IKK inhibitor suppresses heart failure and chronic remodeling after myocardial ischemia via MMP alteration. , 2008, Expert opinion on therapeutic targets.

[64]  M. Yao,et al.  A selective IKK-2 inhibitor blocks NF-kappa B-dependent gene expression in interleukin-1 beta-stimulated synovial fibroblasts. , 2003, The Journal of biological chemistry.

[65]  S. Keslacy,et al.  Inhibition of Tumor Necrosis Factor-α-Inducible Inflammatory Genes by Interferon-γ Is Associated with Altered Nuclear Factor-κB Transactivation and Enhanced Histone Deacetylase Activity , 2006, Molecular Pharmacology.

[66]  K. Chung,et al.  Validation of the Anti-Inflammatory Properties of Small-Molecule IκB Kinase (IKK)-2 Inhibitors by Comparison with Adenoviral-Mediated Delivery of Dominant-Negative IKK1 and IKK2 in Human Airways Smooth Muscle , 2006, Molecular Pharmacology.

[67]  A. Itai,et al.  A Novel IκB Kinase-β Inhibitor Ameliorates Bleomycin-induced Pulmonary Fibrosis in Mice , 2006 .

[68]  N. Munshi,et al.  NF-kappa B as a therapeutic target in multiple myeloma. , 2002, The Journal of biological chemistry.

[69]  S. Ghosh,et al.  Amelioration of acute inflammation by systemic administration of a cell-permeable peptide inhibitor of NF-kappaB activation. , 2005, Arthritis and rheumatism.

[70]  K. L. Gardner,et al.  Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy. , 2007, The Journal of clinical investigation.

[71]  T. Ogihara,et al.  In vivo transfection of cis element “decoy” against nuclear factor- κB binding site prevents myocardial infarction , 1997, Nature Medicine.

[72]  C. Trautwein,et al.  Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis , 2008, Gut.

[73]  N. Matsuda,et al.  Nuclear Factor-κB Decoy Oligodeoxynucleotides Prevent Acute Lung Injury in Mice with Cecal Ligation and Puncture-Induced Sepsis , 2005, Molecular Pharmacology.

[74]  S. Iida,et al.  Growth Inhibition of Multiple Myeloma Cells by a Novel IκB Kinase Inhibitor , 2005, Clinical Cancer Research.

[75]  C. Hunter,et al.  NF-κB Family of Transcription Factors: Central Regulators of Innate and Adaptive Immune Functions , 2002, Clinical Microbiology Reviews.

[76]  K. McIntyre,et al.  BMS-345541 is a highly selective inhibitor of I kappa B kinase that binds at an allosteric site of the enzyme and blocks NF-kappa B-dependent transcription in mice. , 2003, The Journal of biological chemistry.

[77]  V. Imbert,et al.  AS602868, a pharmacological inhibitor of IKK2, reveals the apoptotic potential of TNF-α in Jurkat leukemic cells , 2003, Oncogene.

[78]  T. Niki,et al.  A selective novel low-molecular-weight inhibitor of IkappaB kinase-beta (IKK-beta) prevents pulmonary inflammation and shows broad anti-inflammatory activity. , 2005, British journal of pharmacology.

[79]  Koji Okabe,et al.  Selective inhibition of NF-κB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo , 2004, Nature Medicine.

[80]  T. Ogihara,et al.  Intravenous injection of oligodeoxynucleotides to the NF-kappaB binding site inhibits hepatic metastasis of M5076 reticulosarcoma in mice , 2001, Gene Therapy.

[81]  Ruhang Tang,et al.  IKKβ inhibition attenuates myocardial injury and dysfunction following acute ischemia-reperfusion injury , 2007 .

[82]  F. Greten,et al.  IKK/NF‐κB and STAT3 pathways: central signalling hubs in inflammation‐mediated tumour promotion and metastasis , 2009, EMBO reports.

[83]  B. Ma,et al.  Inhibition of NF-kappaB activation reduces the tissue effects of transgenic IL-13. , 2007, Journal of immunology.

[84]  S. Iida,et al.  Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor , 2006, Leukemia.

[85]  L. Staudt,et al.  Small molecule inhibitors of IκB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling , 2005 .

[86]  K. Anderson,et al.  Cytokines modulate telomerase activity in a human multiple myeloma cell line. , 2002, Cancer research.

[87]  N. Munshi,et al.  CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling. , 2003, Blood.

[88]  J. Pober,et al.  Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. , 2000, Science.

[89]  A. Itai,et al.  Aldosterone-induced kidney injury is mediated by NFκB activation , 2010, Clinical and Experimental Nephrology.

[90]  A. Itai,et al.  Inhibition of IκB phosphorylation in cardiomyocytes attenuates myocardial ischemia/reperfusion injury , 2004 .

[91]  B. Ma,et al.  Inhibition of NF-κB Activation Reduces the Tissue Effects of Transgenic IL-131 , 2007, The Journal of Immunology.

[92]  Fajun Yang,et al.  The green tea polyphenol (-)-epigallocatechin-3-gallate blocks nuclear factor-kappa B activation by inhibiting I kappa B kinase activity in the intestinal epithelial cell line IEC-6. , 2001, Molecular pharmacology.

[93]  T. Yoshino,et al.  Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents. , 2004, Bioorganic & medicinal chemistry letters.

[94]  S. Iida,et al.  Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[95]  S. Ghosh,et al.  The NF-kappaB family of transcription factors and its regulation. , 2009, Cold Spring Harbor perspectives in biology.

[96]  P. Richardson,et al.  Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines , 2003, Oncogene.

[97]  C. Sawyers,et al.  IκB kinase β inhibition induces cell death in Imatinib-resistant and T315I Dasatinib-resistant BCR-ABL+ cells , 2008, Molecular Cancer Therapeutics.

[98]  R. Weichselbaum,et al.  Diverse TNFα-induced death pathways are enhanced by inhibition of NF-κB , 2007 .

[99]  M. Isobe,et al.  Tea catechins improve left ventricular dysfunction, suppress myocardial inflammation and fibrosis, and alter cytokine expression in rat autoimmune myocarditis , 2007, European journal of heart failure.

[100]  Y. Chiba,et al.  IL-13 induces translocation of NF-kappaB in cultured human bronchial smooth muscle cells. , 2009, Cytokine.

[101]  A. Itai,et al.  Topical application with a new NF-kappaB inhibitor improves atopic dermatitis in NC/NgaTnd mice. , 2007, The Journal of investigative dermatology.

[102]  B. Mellado,et al.  Interleukin 6, a Nuclear Factor-κB Target, Predicts Resistance to Docetaxel in Hormone-Independent Prostate Cancer and Nuclear Factor-κB Inhibition by PS-1145 Enhances Docetaxel Antitumor Activity , 2006, Clinical Cancer Research.