Jed F Fisher1, Shahriar Mobashery. 1. Department of Chemistry and Biochemistry, Walther Cancer Research Center, University of Notre Dame, Notre Dame, IN, USA.
Abstract
The recognition that the successful clinical use of MMP inhibitors will require quantitative correlation of MMP activity with disease type, and to disease progression, has stimulated intensive effort toward the development of sensitive assay methods, improved analytical methods for the determination of the structural profile for MMP-sub-type inhibition, and the development of new methods for the determination - in both quantitative and qualitative terms - of MMP activity. This chapter reviews recent progress toward these objectives, with particular emphasis on the quantitative and qualitative profiling of MMP activity in cells and tissues. Quantitative determination of MMP activity is made from the concentration of the MMP from the tissue, using immobilization of a broad-spectrum MMP inhibitor on a chromatography resin. Active MMP, to the exclusion of MMP zymogens and endogenous TIMP-inhibited MMPs, is retained on the column. Characterization of the MMP sub-type(s) follows from appropriate analysis of the active MMP eluted from the resin. Qualitative determination of MMP involvement in disease can be made using an MMP sub-type-selective inhibitor. The proof of principle, with respect to this qualitative determination of the disease involvement of the gelatinase MMP-2 and MMP-9 sub-types, is provided by the class of thiirane-based MMP mechanism-based inhibitors (SB-3CT as the prototype). Positive outcomes in animal models of disease having MMP-2 and/or -9 dependency follow administration of this MMP inhibitor, whereas this inhibitor is inactive in disease models where other MMPs (such as MMP-14) are involved.
The recognition that the successful clinical use of MMP inhibitors will require quantitative correlation of n class="Gene">MMP activity with disease type, and to disease progression, has stimulated intensive effort toward the development of sensitive assay methods, improved analytical methods for the determination of the structural profile for MMP-sub-type inhibition, and the development of new methods for the determination - in both quantitative and qualitative terms - of MMP activity. This chapter reviews recent progress toward these objectives, with particular emphasis on the quantitative and qualitative profiling of MMP activity in cells and tissues. Quantitative determination of MMP activity is made from the concentration of the MMP from the tissue, using immobilization of a broad-spectrum MMP inhibitor on a chromatography resin. Active MMP, to the exclusion of MMP zymogens and endogenous TIMP-inhibited MMPs, is retained on the column. Characterization of the MMP sub-type(s) follows from appropriate analysis of the active MMP eluted from the resin. Qualitative determination of MMP involvement in disease can be made using an MMP sub-type-selective inhibitor. The proof of principle, with respect to this qualitative determination of the disease involvement of the gelatinase MMP-2 and MMP-9 sub-types, is provided by the class of thiirane-based MMP mechanism-based inhibitors (SB-3CT as the prototype). Positive outcomes in animal models of disease having MMP-2 and/or -9 dependency follow administration of this MMP inhibitor, whereas this inhibitor is inactive in disease models where other MMPs (such as MMP-14) are involved.
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