Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.
PR Newswire, 810 Seventh Avenue, New York, NY 10019 - Friday, 1 November 1996
The p38 MAP kinase is a member of a family of structurally-related human enzymes involved in intracellular signaling pathways that enable cells to respond to their environment. When activated, the p38 MAP kinase triggers production of interleukin-1 (IL-1) and tumor necrosis factor (TNF), cytokines that play a central role in the body's inflammatory response. Excess levels of IL-1 and TNF are associated with a broad range of acute and chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, inflammatory bowel disease, asthma, atherosclerosis, and cachexia. IL-1 and TNF also play an important role in programmed cell death associated with ischemia and stroke, and in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.
"The p38 MAP kinase is an excellent target for drug discovery based on its ability to regulate two major pro-inflammatory mediators," commented Michael S.-S. Su, Ph.D., Senior Scientist and Project Head for Vertex's MAP kinase program. "In addition, several published reports validate p38 MAP kinase as a drug target. In an experiment that mimicked p38 MAP kinase inhibition, co- administration of biological inhibitors of IL-1 and TNF completely prevented bone loss in a model of osteoarthritis. Further research illustrates that prototype inhibitors of p38 MAP kinase reduce symptoms of acute and chronic inflammatory diseases in a variety of animal models."
Vertex scientists determined the three-dimensional structure of p38 MAP kinase using X-ray crystallography. This biophysical technique determines accurately the position of every atom of the enzyme. The structure locates the active site of p38 MAP kinase and reveals the shape of the binding site for the co-factor molecule ATP. In addition, the structure shows that p38 MAP kinase contains a molecular "gate" that uncovers the active site when the enzyme is activated.
"The structure of p38 MAP kinase has allowed us to understand how various inhibitors bind to p38 MAP kinase and related kinases," said Keith Wilson, Ph.D., Senior Scientist and Head of Vertex's crystallography group. "This information about the features of the enzyme is proving to be very useful in drug design."
"Since initiating our MAP kinase program less than one year ago, we have made rapid progress to generate structural information on p38 MAP kinase as a target for novel anti-inflammatory drugs," said Dr. Vicki Sato, Senior Vice President of Research and Development and Chief Scientific Officer of Vertex. "The p38 MAP kinase is a member of a family of molecules that regulate signal transduction in cells. Based on the role of these molecules in the body, we believe MAP kinases should provide a rich area for identifying further drug targets."
"Vertex has made important strides in drug discovery research during 1996," commented Dr. Joshua Boger, Vertex President and Chief Executive Officer. "In addition to p38 MAP kinase, Vertex researchers have published the structures of hepatitis C protease, a target for new drugs to treat hepatitis C infection, and IMPDH (inosine monophosphate dehydrogenase), a target for new immunosuppressive drugs. These accomplishments, together with progess in compound design and target validation, underscore the productivity of Vertex's drug discovery research."
The authors of The Journal of Biological Chemistry paper are Keith P. Wilson, Matthew J. Fitzgibbon, Paul R. Caron, James P. Griffith, Wenyong Chen, Patricia G. McCaffrey, Steven P. Chambers and Michael S.-S. Su, all of Vertex.
Vertex Pharmaceuticals Incorporated is engaged in the discovery, development and commercialization of novel, small molecule pharmaceuticals for the treatment of diseases for which there are currently limited or no effective treatments. The Company is a leader in the use of structure-based drug design, an approach to drug discovery that integrates advanced biology, biophysics and chemistry. The Company is concentrating on the discovery and development of drugs for the treatment of viral diseases, multidrug resistance in cancer, hemoglobin disorders, inflammation, autoimmune diseases, organ transplant rejection and neurodegenerative diseases.
CONTACT: Lynne H. Brum, Director of Corporate Communications of Vertex, 617-577-6000 or http://www.vpharm.com
Copyright (c) 1996/PR NewsWire. Reproduced with permission. Reproduction of this article (other than one copy for personal reference) must be cleared through the Permissions Desk, PR Newswire, 810 Seventh Avenue, New York, NY 10019.
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