The studies outlined in this proposal are a continuation of our effort towards achieving the long-term goal of developing novel approaches to selective inhibition of matrix metalloproteinase (MMP) activity during cancer progression. In the previous funding period we focused on the gelatinases, MMP-2 and MMP-9 and we reported the successful development and characterization of the first mechanism-based gelatinase inhibitor, SB-3CT, and demonstrated its effectiveness in various tumor models in mice. Our approach to selective MMP inhibitor design has provided a point of departure for the field. We now propose to develop this approach for effective and selective inhibition of membrane-type MMPs (MT-MMP), a subfamily of membrane-anchored MMPs that has received considerable attention in the last five years due to their key roles in cancer cell invasion. This new information highlights the MT-MMPs as promising therapeutic targets that deserve further exploration. However, to achieve this goal there is critical need for effective and selective MT-MMP inhibitors, which are currently missing. Preliminary evidence from our laboratory demonstrates the development of new mechanism-based MT1-MMP inhibitors with great potential. Also, a novel inhibitor library has been conceived, which will permit discovery of more selective mechanism-based inhibitors for MT-MMPs based on the molecular template of SB-3CT. Finally, to aid in the detection of active MMPs in cancer tissues, we have synthesized and tested an inhibitor-tethered resin, which can be used to ascertain the level of active protease during cancer progression and inhibitor treatment. Here we propose to continue our effort using a comprehensive approach of biochemical and biological studies for identification and inhibition of MT-MMPs. Specifically, we will (1) Identify selective mechanism-based inhibitors for transmembrane MT-MMPs, (2) Validate the inhibitory properties of the MT-MMP inhibitors in cellular systems of MT-MMP-dependent pericellular proteolysis, (3) Test the MT-MMP inhibitors in animal models of cancer, and (4) Monitor active forms of the MT-MMP/gelatinase axis in tumor tissues as a function of tumor development and MT-MMP inhibitor treatment. The results of the present application will contribute to the collective endeavor of developing novel and rational approaches for controlling unregulated proteolysis in cancer tissues mediated by MT-MMPs.

Public Health Relevance

Tumor dissemination and metastasis remain the major cause of death in cancer patients. Therefore, understanding the biological factors promoting these processes and developing therapies aimed at reducing tumor spread is of great clinical significance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100475-09
Application #
8444682
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Snyderwine, Elizabeth G
Project Start
2003-07-01
Project End
2014-07-31
Budget Start
2013-02-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$303,871
Indirect Cost
$53,149
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Lee, Mijoon; Celenza, Giuseppe; Boggess, Bill et al. (2009) A potent gelatinase inhibitor with anti-tumor-invasive activity and its metabolic disposition. Chem Biol Drug Des 73:189-202
Gooyit, Major; Lee, Mijoon; Hesek, Dusan et al. (2009) Synthesis, kinetic characterization and metabolism of diastereomeric 2-(1-(4-phenoxyphenylsulfonyl)ethyl)thiiranes as potent gelatinase and MT1-MMP inhibitors. Chem Biol Drug Des 74:535-46
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Gu, Zezong; Cui, Jiankun; Brown, Stephen et al. (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25:6401-8
Lee, Mijoon; Bernardo, M Margarida; Meroueh, Samy O et al. (2005) Synthesis of chiral 2-(4-phenoxyphenylsulfonylmethyl)thiiranes as selective gelatinase inhibitors. Org Lett 7:4463-5
Kruger, Achim; Arlt, Matthias J E; Gerg, Michael et al. (2005) Antimetastatic activity of a novel mechanism-based gelatinase inhibitor. Cancer Res 65:3523-6

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