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Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth.

ABSTRACT: Membrane type-1 matrix metalloproteinase (MT1-MMP) is a promising drug target in malignancy. The structure of MT1-MMP includes the hemopexin domain (PEX) that is distinct from and additional to the catalytic domain. Current MMP inhibitors target the conserved active site in the catalytic domain and, as a result, repress the proteolytic activity of multiple MMPs instead of MT1-MMP alone. In our search for noncatalytic inhibitors of MT1-MMP, we compared the protumorigenic activity of wild-type MT1-MMP with an MT1-MMP mutant lacking PEX (?PEX). In contrast to MT1-MMP, ?PEX did not support tumor growth in vivo, and its expression resulted in small fibrotic tumors that contained increased levels of collagen. Because these findings suggested an important role for PEX in tumor growth, we carried out an inhibitor screen to identify small molecules targeting the PEX domain of MT1-MMP. Using the Developmental Therapeutics Program (National Cancer Institute/NIH), virtual ligand screening compound library as a source and the X-ray crystal structure of PEX as a target, we identified and validated a novel PEX inhibitor. Low dosage, intratumoral injections of PEX inhibitor repressed tumor growth and caused a fibrotic, ?PEX-like tumor phenotype in vivo. Together, our findings provide a preclinical proof of principle rationale for the development of novel and selective MT1-MMP inhibitors that specifically target the PEX domain.

SUBMITTER: Remacle AG

PROVIDER: S-EPMC3342448 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth.

Remacle Albert G AG Golubkov Vladislav S VS Shiryaev Sergey A SA Dahl Russell R Stebbins John L JL Chernov Andrei V AV Cheltsov Anton V AV Pellecchia Maurizio M Strongin Alex Y AY

Cancer research 20120309 9

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a promising drug target in malignancy. The structure of MT1-MMP includes the hemopexin domain (PEX) that is distinct from and additional to the catalytic domain. Current MMP inhibitors target the conserved active site in the catalytic domain and, as a result, repress the proteolytic activity of multiple MMPs instead of MT1-MMP alone. In our search for noncatalytic inhibitors of MT1-MMP, we compared the protumorigenic activity of wild-type MT1 ...[more]

PMID: 22406620

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Project description:BackgroundMMP-13, a zinc dependent protease which catalyses the cleavage of type II collagen, is expressed in osteoarthritis (OA) and rheumatoid arthritis (RA) patients, but not in normal adult tissues. Therefore, the protease has been intensively studied as a target for the inhibition of progression of OA and RA. Recent reports suggest that selective inhibition of MMP-13 may be achieved by targeting the hemopexin (Hpx) domain of the protease, which is critical for substrate specificity. In this study, we applied a cheminformatics-based drug design approach for the identification and characterization of inhibitors targeting the amino acid residues characteristic to Hpx domain of MMP-13; these inhibitors may potentially be employed in the treatment of OA and RA.Methodology/principal findingsSequence-based mutual information analysis revealed five characteristic (completely conserved and unique), putative functional residues of the Hpx domain of MMP-13 (these residues hereafter are referred to as HCR-13(pf)). Binding of a ligand to as many of the HCR-13(pf) is postulated to result in an increased selective inhibition of the Hpx domain of MMP-13. Through the in silico structure-based high-throughput virtual screening (HTVS) method of Glide, against a large public library of 16908 molecules from Maybridge, PubChem and Binding, we identified 25 ligands that interact with at least one of the HCR-13(pf). Assessment of cross-reactivity of the 25 ligands with MMP-1 and MMP-8, members of the collagenase family as MMP-13, returned seven lead molecules that did not bind to any one of the putative functional residues of Hpx domain of MMP-1 and any of the catalytic active site residues of MMP-1 and -8, suggesting that the ligands are not likely to interact with the functional or catalytic residues of other MMPs. Further, in silico analysis of physicochemical and pharmacokinetic parameters based on Lipinski's rule of five and ADMET (absorption, distribution, metabolism, excretion and toxicity) respectively, suggested potential utility of the compounds as drug leads.Conclusions/significanceWe have identified seven distinct drug-like molecules binding to the HCR-13(pf) of MMP-13 with no observable cross-reactivity to MMP-1 and MMP-8. These molecules are potential selective inhibitors of MMP-13 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for OA, RA and other inflammatory disorders. The systematic cheminformatics-based drug design approach applied herein can be used for rational search of other public/commercial combinatorial libraries for more potent molecules, capable of selectively inhibiting the collagenolytic activity of MMP-13.

Dataset Information

Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth.

Publications

Novel MT1-MMP small-molecule inhibitors based on insights into hemopexin domain function in tumor growth.

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