A number of diseases manifest their pathology by degradation of the matrix surrounding tissues. Two of these diseases, targets of investigation by this grant application, are stroke and metastatic cancer. Evidence has shown that members of the matrix metalloproteinase (MMP) family of zinc-dependent endopeptidases, of which 26 are known, play key roles in these processes. In particular, there is clear indication that gelatinases (MMP-2 and MMP-9) are major contributors. Broad-spectrum synthetic MMP inhibitors were shown to be effective anti-cancer agents in animal models of cancer, but produced serious side effects in clinical trials in patients with advanced cancer. Broad inhibitory properties of these inhibitors against all MMPs and several related metalloproteinases have been postulated as one of the major reasons for the difficulties and the undesired side effects. We have answered this challenge and have devised the first mechanism-based (suicide) inhibitor (inhibitor 1) that is highly selective for gelatinases (MMP-2 and MMP-9), as evidenced by in vitro investigations with purified enzymes. Inhibitor 1 is also active in rodent models for two distinct cancers and stroke. Despite the early promise of inhibitor 1, the molecule is not poised to move forward, as it is poorly water soluble and it is readily metabolized. The science disclosed herein is intended to devise the next generation of this type of inhibitor with attention to improved selectivity in targeting, better aqueous solubility, desirable pharmacokinetic properties and lead optimization, which would move the project in the direction of preclinical development and subsequent entry into clinical trials. The clinical needs for intervention of stroke and of aggressive metastatic cancers are genuine. The science disclosed herein holds promise in meeting the clinical challenges. When cancer spreads in the body (metastasis), it becomes a fatal disease. Similarly, stroke is a big killer in the community. Spread of cancer and brain damage after stroke share a number of characteristics that are the subjects of this grant application. The grant applicants have developed a class of molecules that prevent cancer from spreading and prevent brain cell death due to stroke. The present grant application attempts to bring forward members of this type of drug forward for preclinical development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122417-05
Application #
8119558
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2007-09-07
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$364,376
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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Zhang, Haoqian; Chang, Mayland; Hansen, Christopher N et al. (2011) Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury. Neurotherapeutics 8:206-20
Testero, Sebastian A; Bouley, Renee; Fisher, Jed F et al. (2011) Exploration of mild copper-mediated coupling of organotrifluoroborates in the synthesis of thiirane-based inhibitors of matrix metalloproteinases. Bioorg Med Chem Lett 21:2675-8
Sohail, Anjum; Marco, Marta; Zhao, Huiren et al. (2011) Characterization of the dimerization interface of membrane type 4 (MT4)-matrix metalloproteinase. J Biol Chem 286:33178-89
Benson, Heather L; Mobashery, Shahriar; Chang, Mayland et al. (2011) Endogenous matrix metalloproteinases 2 and 9 regulate activation of CD4+ and CD8+ T cells. Am J Respir Cell Mol Biol 44:700-8

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