FOR IMMEDIATE RELEASE
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 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
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 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.