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Volume 3 Issue 154 Published - 14:00 UTC 08:00 EST 7-Sep-2001 Next Update - 14:00 UTC 08:00 EST 8-Sep-2001
| Editor: Susan K. Boyer, RN © RAmEx Ars Medica, Inc. All rights reserved. |
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 Structure Of Integrin Alpha-V-Beta-3 Revealed - Protein Key To The Next Generation of Cancer Drugs
After five years of transatlantic collaboration, researchers of Merck KGaA and the Massachusetts General Hospital (MGH) have solved, for the first time ever, the full structure of an integrin receptor. This key protein plays a major role in the control of biological processes and diseases, ranging from cancer to restenosis, osteoporosis, rheumatism and inflammation. The important findings of the research team, which will appear in Science Magazine, were published today on the Science Express website (http://www.scienceexpress.org). "This is the first look anyone has had at the whole structure of an integrin, and it reveals wholly unexpected aspects that may lead to innovative therapeutics," said Dr. Inge Lues, Vice President, Preclinical R&D at Merck KGaA. "This scientific breakthrough is a result of our strong commitment to cutting edge research in oncology, and international collaborations with world class investigators," Lues added. "Knowing the shape of this receptor will help us all develop new strategies to target many serious diseases," says M. Amin Arnaout, MD, Director of the Structural Biology Program at MGH and Chief of the MGH Renal Unit. The MGH team of researchers, headed by Dr. Anaout, has been trying to decipher the three dimensional structure of this particular integrin receptor for several years. Integrin receptors transmit chemical signals from a cell's surface into its interior, which regulate most cellular processes such as attachment, proliferation, differentiation, and survival. Integrin alpha-v-beta-3, for which the full structure now has been resolved, is one of the therapeutically most exiting members of this receptor family. In a novel therapeutic approach to fight cancer, researchers try to specifically block this integrin receptor which is located on the surface of endothelial cells. Solid tumors activate these cells to promote the sprouting of new blood vessels that connect the tumor to the main circulating system. This process, which enables the tumor to grow and metastasise, can be blocked by a specific integrin inhibitor called Cilengitide. This new drug candidate, now in Phase II clinical trials, binds specifically to an integrin, resulting in death of activated endothelial cells, reduced blood vessel formation within the tumor and ultimately inhibition of tumor growth and metastasis. "The better you know the precise shape of the binding site of the integrin, the better you are able to design specific inhibitors, which may result in novel drugs," said Merck KGaA researcher Dr. Simon L. Goodman, who, together with Dr. Reinhardt Dunker and Dr. Beate Diefenbach, succeeded in producing gram amounts of the receptor molecule at an ultra high purity level by applying recombinant cDNA technology. This was the essential prerequisite for the MGH scientists to generate crystals of the integrin receptor in sufficient quality. By the end of 2000, in a very competitive field, they finally solved the full structure of the receptor by X-ray crystallography. |
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