Therapeutic modulation of inflammatory gene transcription by kinase inhibitors.
Altered gene expression contributes to the aetiology of inflammatory disease by modulation of the concentration of disease-related proteins. The expression of inflammatory genes is controlled through the concerted actions of specific transcription factors. Signal transduction networks positively or negatively regulate the activity of these transcription factors. Key components of these networks are protein kinases, which phosphorylate substrates on tyrosine, threonine or serine residues. During the disease process, pro-inflammatory signalling at the cell surface leads to a cascade of kinase activation, which ultimately culminates in modulation of the activity of transcription factors. Thus, pharmacological inhibition of protein kinases is a potential therapeutic strategy to treat inflammation. There are approximately 500 protein kinases in the human genome. Targeted small molecule inhibitors of these kinases should allow for tissue- and disease-specific therapies of unprecedented selectivity. Heralding this new era in molecular medicine is imatinib (Gleevec, Norvartis) a recently marketed tyrosine kinase inhibitor. This review focuses on kinase inhibitors that are currently in development for inflammatory diseases and the transcription factors that are involved.
Alton
Gordon
G
Biochemistry Department, Pfizer Global Research and Development, La Jolla Laboratories, 4215 Sorrento Valley Boulevard, San Diego, CA 92121, USA. galton@pfizer.com
Schwamborn
Klaus
K
Satoh
Yoshi
Y
Westwick
John K
JK
D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000628:therapy*; D008954:Models, Biological; D008956:Models, Chemical; D010766:Phosphorylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014158:Transcription, Genetic
D004791:Enzyme Inhibitors; D010770:Phosphotransferases