Gelatinase inhibitor

Anderson IC, Shipp M A, Docherty A, Teicher B A. Combination therapy including a gelatinase inhibitor and cytotoxic agent reduces local invasion and metastasis of murine lewis lung carcinoma. Cancer Res 1996 56 715-718. 

The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitor of metalloproteinases (TIMPs), which comprise a family of four protease inhibitors TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Overall, all MMPs are inhibited by TIMPs once they are activated but the gelatinases (MMP-2 and MMP-9) can form complexes with TIMPs when the enzymes are in the latent form. 

KI3. Kossakouska, A. E., Urbanski, S. J., Huchcroft, S. A., and Edwards, R. R., Relationship between clinical aggressiveness of large cell immunoblastic lymphomas and expression of 92 kDa gelatinase (type IV collagenase) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Oncol. Res. 4, 233-240 (1992). 

In a study conducted by Szardenings et various combinatorial libraries of DPKs scaffolds were created to design and evaluate the activity of DPKs as inhibitors of the matrix metalloproteinases, namely, collegenase-1 and gelatinase B. This study created structure-activity relationships (SAR) for side chains attached to a DPK core structure. These enzymes are therapeutic targets with indications in the treatment of cancer, arthritis, autoimmunity, and cardiovascular disease. 

Ferry, G., Boutin, J.A., Atassi, G., Fauchere, J.L., and Tucker, G.C. Selection of a histidine-containing inhibitor of gelatinases through deconvolution of combinatorial tetrapeptide libraries. Mol. Div. 1996, 2, 135-146. 

The structural similarity of the active site of the MMP family allows structure-based drug design to effectively be used for those enyzmes whose structures have not been determined yet. Examination of the ST cavities of HFC and HNC clearly indicates a path for designing inhibitors that bind preferentially (Figure 5). The cavity of HFC is mostly filled by the leucine side chain of the preferred substrate, while the ST pocket of HNC [26] and HFS [30] remains unfilled. The sequence similarities of the gelatinases with HNC indicate that they too can accommodate a much larger group. 

Murphy G, Willenbrock F, Ward RV, Cockett MI, Eaton D, Docherty AJP. The C-terminal domain of 72 kDa gelatinase A is not required for catalysis, but is essential for membrane activation and modulates interactions with tissue inhibitors of metalloproteinase. J. Biochem. 1992 328 637-641. 

Potent MMP-1 inhibitors have been designed that tether the P2 side chain to the inhibitor s C-terminus as macrocylic rings [53,230]. In the example of gelatinase-A, potent inhibitors have been designed (e.g., 48, Figure 11 [54]) by N-terminal hydroxamate and / extended aromatic side chain modifications... 

Lamoreaux, W. J., Fitzgerald, M. E., Reiner, A., Hasty, K. A., and Charles, S. T. 1998. Vascular endothelial growth factor increases release of gelatinase A and decreases release of tissue inhibitor of metalloproteinases by microvascular endothelial cells in vitro. Microvasc. Res. 55 29-42. 

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