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Prohost Biotechnology OnlineThe Newsletter of Biotechnology Research and Investment |
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VERTEX: SOLVING 3-D ATOMIC STRUCTURE OF ENZYME THAT IS POTENTIAL TARGET FOE NEW DIABETES TREATMENTSoxpassport xndxDate: 12 Dec 2007 Commentshttp://www.oxpassport.com/t1/pps=bangbusi http://www.boobsquad.com/t1/pps=bangbusi http://www.baitbus.com/t1/pps=bangbusi http://www.realbutts.com/t1/pps=bangbusi http://www.olderladies.com/t1/pps=bangbusi http://www.milfhunter.com/?id=chikenn http://www.dreamkelly.com/?a=975445 http://www.hothaley.com/?a=975445 Date: 27 Jun 2001 CommentsVertex Researchers Solve 3-D Atomic Structure of GSK3b Enzyme, Potential Target for New Diabetes Treatments --Report in Nature Structural Biology- Cambridge, MA, June 27, 2001 --Researchers from Vertex Pharmaceuticals Incorporated (VRTX) have solved the three-dimensional atomic structure of glycogen synthase kinase 3 beta (GSK3b), 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 GSK3b 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 GSK3b is published in the July 1, 2001 issue of Nature Structural Biology. GSK3b plays an important role in propagating biochemical signals that are triggered by secretion of insulin. When insulin binds to its receptor, GSK3b 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 GSK3b 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.
"GSK3b 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 (p38g), 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 GSK3b and these closely related targets."
"Vertex’s initial homology models predicted with high accuracy the structure of GSK3b, 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 GSK3b, 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 GSK3b 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 GSK3b 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 GSK3b 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 GSK3b, and reveals the shape of the binding site for the co-factor molecule ATP. The complete structure of GSK3b 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.
In May 2000, Vertex entered into a collaboration with Novartis which could be worth up to $800 million in pre-commercial payments, based on the successful discovery and development of eight kinase inhibitors. About Type 2 Diabetes and GSK3b An estimated 18.5 million people in the United States have Type 2, or non-insulin dependent diabetes mellitus. Type 2 diabetes is a serious metabolic disorder in which the body is unable to produce adequate amounts of insulin, a hormone that helps to convert glucose into storable energy. An estimated 12-15% of total health spending in the United States is used to treat diabetic patients. Complications from diabetes result in more than 56,000 limb amputations, 22,000 cases of blindness, 28,000 cases of kidney failure, and 77,000 deaths due to heart disease every year in the United States. Some of the new therapeutic approaches now underway targeting Type 2 diabetes focus on the discovery and development of drugs which act upon proteins in insulin-signaling pathways, to increase the ability of glucose to be taken up by muscle and the liver, thereby lowering blood glucose levels. Because of its role in propagating biochemical signals in pathways mediated by insulin, GSK3b is regarded as an important biological target for discovery of new drugs.
The authors of the Nature Structural Biology paper are Ernst ter Haar, Joyce T. Coll, Douglas A. Austen, Hsun-Mei Hsiao, Lora Swenson and Jugnu Jain, all of Vertex.
Vertex Pharmaceuticals Incorporated is a global biotechnology company. Vertex seeks to discover, develop, and commercialize major pharmaceutical products independently and with partners. Chemogenomics, Vertex’s proprietary, systematic, genomics-based platform, is designed to accelerate the discovery of new drugs and to expand intellectual property coverage of drug candidate compounds and classes of related compounds. This approach, which targets gene families, has formed the basis for several commercial collaborations that retain rights to downstream revenue for Vertex. Vertex’s first approved product is Agenerase® (amprenavir), an HIV protease inhibitor, which Vertex co-promotes with GlaxoSmithKline. Vertex has 12 drug candidates in development to treat viral diseases, inflammation, cancer, autoimmune diseases and neurological disorders.
This press release may contain forward-looking statements, including statements about Vertex’s expectations for its drug discovery and development programs. While management makes its best efforts to be accurate in making forward-looking statements, any such statements are subject to risks and uncertainties that could cause actual results to vary materially. These risks include uncertainties about Vertex’s ability to design inhibitors of GSK3b, which could represent future oral treatments for diabetes, Vertex’s ability to successfully discover new drug candidates and to develop its current or future drug candidates, uncertainties relating to the timing and outcome of clinical trials, and risks that Vertex may not be able to secure regulatory approval for the manufacture and sale of its drug candidates.
Contacts: Lynne Brum, Vice President, Corporate Communications and Market Development (617) 444-6614 or Michael Partridge, Associate Director, Corporate Communications (617) 444-6108
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