1999 From: Noonan/Russo Communications
Report in Science on x-ray crystal structure of matrix Metalloproteinase-2 (MMP-2)MMP-2 is a key target for anti-cancer drug development Research Triangle Park, N.C.--June 4, 1999-- BioStratum Incorporated announced today the publication of a paper in the journal SCIENCE (volume 284, pages 1667-1670) reporting the three-dimensional structure of the matrix metalloproteinase-2 (MMP-2), a key molecular target for a number of anti-cancer drug candidates currently in clinical development. This work was completed by one of BioStratum's founding scientists, Dr. Karl Tryggvason of the Karolinska Institute, Stockholm, Sweden. The elucidated structure of MMP-2 provides valuable information on the function and regulation of this important enzyme, and provides for the design of improved MMP-2 specific inhibitors for clinical evaluation. BioStratum owns intellectual property rights to this technology and to new and improved MMP-2 inhibitors that may be identified. Matrix metalloproteinases (MMPs) are involved in tissue growth and wound repair. MMPs work by degrading substances in the extracellular matrix (the area outside of cells) thereby enabling the movement and expansion of cells, the deposition of new extracellular matrix, and the subsequent development of new tissue. MMP-2 acts directly on type IV collagen, a principal component of the basal lamina, a specialized form of the extracellular matrix. The activation of MMPs has been implicated in the invasive growth and spread of tumors. Several clinical studies are in progress evaluating the effectiveness of MMP inhibitors as anti-cancer agents, and many more are projected to enter clinical trials in the near future. The elucidated molecular structure is the culmination of seven years of effort in Dr. Tryggvason?s laboratory. "This advance is providing important insights into the catalytic and regulatory mechanisms of this enzyme. It also provides an additional tool to aid in the design of improved MMP inhibitors to combat the spread of cancer," said Dr. Tryggvason. One of the MMPs, so called gelatinase A, now also referred to as MMP-2, was discovered by Dr. Tryggvason and co-investigator Dr. Lance Liotta at the National Cancer Institute in the early 1980s. These investigators originally proposed a key role for MMP-2 in tumor invasion. They suggested metastasizing tumors up-regulate and/or activate MMP-2, thereby increasing the degradation of type IV collagen, the principal substrate of MMP-2 and the main structural component of the basal lamina, thus providing the means for tumors to traverse tissue barriers. Although originally viewed with skepticism, this role of MMP-2 in tumor invasion has been confirmed by numerous laboratories, and is now a primary target for the development of advanced MMP inhibitors to treat cancer metastasis. Most of the MMP inhibitors that have reached clinical trials exhibit broad activity against many members of the MMP family, now known to total sixteen. This broad specificity could provide for a more effective anti-cancer drug, as a number of MMPs are suspected to participate in matrix degradation during tumor invasion. However, significant side effects in patients have emerged after several months of treatment, suggesting the need for a more specific inhibitor to target the key MMPs principally involved in the growth and spread of cancer, such as MMP-2. Dr. Tryggvason's laboratory is analyzing the three-dimensional configuration of the active site of MMP-2 to identify new small molecule lead compounds for the development of advanced MMP inhibitor drug candidates. In addition, small molecules already identified as possessing MMP-2 inhibitory activity are being analyzed using molecular modeling software to determine what improvements can be made to the molecular structure to increase inhibitor binding affinity and specificity. Furthermore, other sites in addition to the catalytic site are being analyzed to identify compounds that inactivate the function of this enzyme through non-catalytic regulatory mechanisms, thus providing for the identification of a second generation of MMP-2 inhibitors. "This advance and ongoing efforts to identify improved MMP-2 inhibitors is part of BioStratum's basal lamina based cancer program, which includes the Company's potent anti-angiogenesis agent Angiocol," said Dr. Archie Prestayko, President and CEO of BioStratum. "When used in combination with cytotoxic anti-cancer therapies, these new 'non-cytotoxic' drug candidates offer real promise in the fight against cancer." BioStratum Incorporated is a privately held company developing proprietary therapeutics based on recent scientific advances in basal lamina and related technologies. The company's drug candidates are directed against novel basal lamina extracellular targets involved in degenerative and invasive disease processes fundamental to kidney disease, diabetes and cancer. The company has also developed methods for the production of recombinant basal lamina proteins for use in wound repair and advanced tissue regeneration protocols. For more background information see below. For MMP-2 images, contact BioStratum or Noonan/Russo. BioStratum's web site address is www.biostratum.com. This release will also be posted at www.noonanrusso.com. Questions and Answers- 1. What is MMP-2?
MMP-2 is a protein and an enzyme that breaks apart other substances that reside in the "extracellular" matrix, the material that exists between cells and tissues. - 2. What is MMP-2's role in the body?
MMP-2, like other members of the MMP family, is important in new tissue growth and wound repair. One way in which MMPs allow new tissue growth is by clearing space so that new blood vessels can form to bring nutrients essential for new cell growth to the area. MMPs also make room for other materials to be deposited into the area of new tissue growth. - 3. Why is MMP-2 relevant to cancer?
MMPs help cancer spread (metastasize) by clearing a path for the migration of cancer cells. MMPs enable the growth of new blood vessels (angiogenesis) which feed tumor growth. - 4. What therapies have been developed against MMPs to date?
Inhibitors to MMPs can: Decrease metastasis Starve tumors Their drawbacks: To date the MMP inhibitors developed have activity against many members of the MMP family. Therefore after long-term use of the inhibitors, side effects such as joint problems develop because the inhibitors also prevent MMPs from doing their "good work" which consists of helping the body repair itself after normal wear and tear. - 5. What is the use of the crystal structure reported in SCIENCE?
Knowing the structure of MMP-2 will enable more specific MMP-2 inhibitors to be designed. This should avoid the problems of side-effects, because the inhibitors will be able to specifically target MMP-2 rather than all the MMPs and may even be specific enough to target functions of MMP-2 that are relevant to cancer, but not as necessary for normal well-being. CONTACT: BioStratum Incorporated Archie W. Prestayko, Ph.D., President and Chief Executive Officer J. Wesley Fox, Ph.D., Executive Vice President [email protected] 919-572-6515 Noonan/Russo Communications,Inc. Anjani Shah, Ph.D., ext. 340 212-696-4455 [email protected]
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