Targeting protein kinases for the development of anti-inflammatory drugs.
In recent years, protein kinases have become the pharmaceutical industry's most studied class of drug target, and some 10 protein kinase inhibitors have so far been approved for the treatment of cancer. However, whether safe drugs that modulate protein kinase activities can also be developed for the treatment of chronic diseases, where they may need to be taken for decades, is an issue that is still unresolved. A number of compounds that inhibit the p38alpha MAPK have entered clinical trials for the treatment of rheumatoid arthritis and psoriasis, but side effects have prevented their progression to Phase III clinical trials. Here I briefly review the potential problems in targeting p38 MAPK and discuss other protein kinases that regulate the innate immune system, such as Tpl2, MAPKAP-K2/3, MSK1/2 and IRAK4, which may be better targets for the treatment of chronic inflammatory diseases, and NIK, which is an attractive target for the treatment of multiple myeloma, a late stage B-cell malignancy.
Cohen
Philip
P
The MRC Protein Phosphorylation Unit, University of Dundee, The Sir James Black Centre, Dundee, UK. p.cohen@dundee.ac.uk
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004789:Enzyme Activation; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human