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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-
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Contact: J. Wesley Fox, Ph.D.
info@biostratum.com
919-572-6515
Noonan/Russo Communications
4-Jun-1999
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