Targeting I kappa B kinase for the treatment of inflammatory and other disorders.
The nuclear transcription factor NF kappa B plays a critical role in the pathogenesis of a number of human disorders, particularly those with an inflammatory component. Due to the fact that I kappa B kinase (IKK)-catalyzed phosphorylation of I kappa B proteins is an essential step in the signal-induced activation of NF kappa B, targeting this kinase represents a fascinating opportunity to develop novel therapeutics. In this review, the current understanding of the role of IKK/NF kappa B in disease processes will be discussed, along with evidence demonstrating that IKK inhibitors will be efficacious in disorders ranging from rheumatoid arthritis to cancer and diabetes. Potential mechanism-based toxicities will also be discussed.
Burke
James R
JR
Bristol-Myers Squibb Pharmaceutical Research Institute, Immunology, Inflammation and Pulmonary Drug Discovery, PO Box 4000, Route 206 & Provinceline Road, Princeton, NJ 08543, USA. james.burke@bms.com
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006333:Heart Failure / Q000178:diet therapy / Q000503:physiopathology; D006801:Humans; D051550:I-kappa B Kinase; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D014158:Transcription, Genetic / Q000502:physiology; D035602:Transcriptional Elongation Factors; D014777:Virus Diseases / Q000188:drug therapy / Q000503:physiopathology
D002352:Carrier Proteins; C114720:Elp1 protein, human; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D035602:Transcriptional Elongation Factors; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human