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Biotech / Medical : Vertex Pharmaceuticals (VRTX) -- Ignore unavailable to you. Want to Upgrade?

To: Miljenko Zuanic who wrote (509)	6/27/2001 9:42:10 AM
From: nigel bates	Respond to of 1169

CAMBRIDGE, Mass., June 27 /PRNewswire/ -- Researchers from Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX - news) have solved the three-dimensional atomic structure of glycogen synthase kinase 3 beta (GSK3 beta), an enzyme involved in the regulation of blood glucose. As part of a broad effort to design and develop major drugs that target members of the kinase gene family, Vertex scientists are using GSK3 beta structural information to design and optimize small molecule inhibitors of the enzyme, which could represent future oral treatments for Type 2 (non-insulin dependent) diabetes. Vertex's structural determination of GSK3 beta is published in the July 1, 2001 issue of Nature Structural Biology.* (Photo: newscom.com ) GSK3 beta plays an important role in propagating biochemical signals that are triggered by secretion of insulin. When insulin binds to its receptor, GSK3 beta is inactivated, which results in activation of glycogen synthase. Glycogen synthase converts glucose into glycogen, a process that allows the body to store energy. Therapeutic modulation of GSK3 beta activity with a small molecule inhibitor may provide a means to activate glycogen synthase in patients with Type 2 diabetes, who do not otherwise possess adequate insulin activity to control blood glucose. ``GSK3 beta is a target of high interest in the kinase gene family, and it shares some important structural features with several other kinases, including cyclin-dependent kinase 2 (CDK2), p38 gamma (p38 gamma), and extracellular-regulated kinase 2 (ERK2),'' said Ernst ter Haar, Ph.D., Vertex Investigator and a principal author of the study. ``We are now optimizing specific small molecule inhibitors based on our knowledge of the subtle differences between GSK3 beta and these closely related targets.'' ``Vertex's initial homology models predicted with high accuracy the structure of GSK3 beta, enabling us to direct our screening efforts around compound libraries that were likely to produce valuable hits,'' said John Thomson, Ph.D., Vice President of Research at Vertex. ``We have identified several potent lead classes of compounds that inhibit GSK3 beta, and we have now obtained encouraging results that show enhanced glucose control when some of these compounds are dosed orally in a preclinical model of diabetes.'' ``Vertex's progress in designing small molecule inhibitors of GSK3 beta exemplifies the research advances we have made across the kinase gene family since our collaboration with Novartis began a little more than a year ago,'' added Thomson. ``On the basis of our progress with GSK3 beta and other related kinase targets, we anticipate selecting one or more novel kinase inhibitors for development in 2001.'' Vertex researchers solved the three-dimensional structure of human GSK3 beta at a resolution of 2.7 angstroms using X-ray crystallography, a biophysical technique that determines accurately the position of every atom of the enzyme. The structure locates the active site of GSK3 beta, and reveals the shape of the binding site for the co-factor molecule ATP. The complete structure of GSK3 beta was first determined at Vertex. The study was accelerated with the use of a crystallization robot that applied microbatch crystallization methods and enabled researchers to grow crystals in less than one day. This method produces high resolution crystallographic images approximately 5-10 times faster and uses 10 times less protein compared to traditional techniques. Vertex Kinase Program Protein kinases are enzymes that play a key role in propagating biochemical signals in many different biological pathways. As such, kinases represent important control points for small molecule therapeutic intervention. To accelerate drug discovery in the kinase gene family and other gene families, Vertex has pioneered a parallel approach to drug design known as chemogenomics. Through its chemogenomics approach, Vertex groups protein targets according to structural similarity, in order to leverage medicinal chemistry efficiently and increase the output of novel drugs for a variety of major diseases...