Mitogen activated protein kinase inhibitors: where are we now and where are we going?
Orally bioavailable compounds that target key intracellular signalling molecules are receiving increasing attention for the treatment of rheumatic diseases. The mitogen activated protein (MAP) kinases are especially attractive because they regulate both cytokine production and cytokine action. The MAP kinases are expressed and activated in rheumatoid arthritis (RA) synovium. Preclinical studies using MAP kinase inhibitors are very effective in animal models of arthritis, supporting their potential utility in human disease. Although the available data suggest a rationale for MAP kinase blockade, development of drugs has been hampered by toxicity and limited efficacy. Alternative strategies, such as targeting other kinases in the cascade or development of allosteric inhibitors have been proposed. These approaches might permit effective use of MAP kinase inhibitors for the treatment of rheumatic and immune-mediated diseases.
Sweeney
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University of California San Diego School of Medicine, Mail Code 0656, Division of Rheumatology, Allergy and Immunology, 9500 Gilman Drive, La Jolla, CA 92093-0656, USA. gfirestein@ucsd.edu.
Firestein
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D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology; D001327:Autoimmune Diseases / Q000201:enzymology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
D018501:Antirheumatic Agents; D047428:Protein Kinase Inhibitors; D020928:Mitogen-Activated Protein Kinases