Structural Basis for the Highly Selective Inhibition of MMP-13

Engel, C.K.; Pirard, Bernard; Schimanski, Sandra; Kirsch, R.; Habermann, J.; Klingler, Otmar; Schlotte, V.; Weithmann, K. U.; Wendt, K. Ulrich

doi:10.1016/j.chembiol.2004.11.014

Cited by 216 publications

(225 citation statements)

References 43 publications

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“…The specificity loop has often been focused as a hotspot for selective MMP inhibitors because of its high sequence and length variability in different MMPs. Pyrimidine dicarboxamide derivatives are notable examples with low-nanomolar affinity for MMP-13, interacting only with the unique S1′ pocket but not touching the catalytic zinc at all (25).…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

Kang

Zhou

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

208

183

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Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C 82 (OH) 22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C 82 (OH) 22 effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C 82 (OH) 22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C 82 (OH) 22 -MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C 82 (OH) 22 inhibits MMP-9 mainly via an exocite interaction, whereas the wellknown zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C 82 (OH) 22 exhibits specific binding modes near the ligand-specificity loop S1′, thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C 82 (OH) 22 a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.indirect inhibition mode | tumor metastasis | antiangiogenesis |

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Section: Resultsmentioning

confidence: 99%

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

Kang

Zhou

Yang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

208

183

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“…A novel subnanomolar nonchelating MMP13 inhibitor was also reported that binds deeply into the S 1 0 pocket of MMP13 and protrudes into the S 1 0 * side pocket. In this bent conformation, it clamps around a leucyl side chain, which is unique to MMP13 (Engel et al, 2005). However, it is not clear whether these are true allosteric inhibitors or functioning by competing for S 1 0 subsite occupancy in deep pocket MMPs.…”

Section: Exosite Binding and Allosteric Inhibitorsmentioning

confidence: 99%

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

2006

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The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection.

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“…544678-85-5)] was dissolved in DMSO and added with each medium replacement to a final concentration of 10 M; the same volume of DMSO without inhibitor was added to the control cells. This inhibitor has high specificity for MMP-13 and binds to the catalytic domain (8). To inhibit MMP-2 activity, MMP-2 inhibitor [IUPAC name 2-((isopropoxy)-(1,1=-biphenyl-4-ylsulfonyl)-amino))-N-hydroxyacetamide (catalog no.…”

Section: Muscle Injury Modelsmentioning

confidence: 99%

Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration

Lei

Leong

Smith

et al. 2013

American Journal of Physiology-Cell Physiology

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Lei H, Leong D, Smith LR, Barton ER. Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration. Am J Physiol Cell Physiol 305: C529-C538, 2013. First published June 12, 2013 doi:10.1152/ajpcell.00051.2013.-Efficient skeletal muscle repair and regeneration require coordinated remodeling of the extracellular matrix (ECM). Previous reports have indicated that matrix metalloproteinases (MMPs) play the pivotal role in ECM remodeling during muscle regeneration. The goal of the current study was to determine if the interstitial collagenase MMP-13 was involved in the muscle repair process. Using intramuscular cardiotoxin injections to induce acute muscle injury, we found that MMP-13 expression and activity transiently increased during the regeneration process. In addition, in muscles from mdx mice, which exhibit chronic injury, MMP-13 expression and protein levels were elevated. In differentiating C2C12 cells, a murine myoblast cell line, Mmp13 expression was most pronounced after myoblast fusion and during myotube formation. Using pharmacological inhibition of MMP-13 to test whether MMP-13 activity is necessary for the proliferation, differentiation, migration, and fusion of C2C12 cells, we found a dramatic blockade of myoblast migration, as well as a delay in differentiation. In contrast, C2C12 cells with stable overexpression of MMP-13 showed enhanced migration, without affecting myoblast maturation. Taken together, these results support a primary role for MMP-13 in myoblast migration that leads to secondary effects on differentiation.collagenase; matrix metalloproteinase; muscle repair; myoblast maturation

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Structural Basis for the Highly Selective Inhibition of MMP-13

Cited by 216 publications

References 43 publications

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration

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Structural Basis for the Highly Selective Inhibition of MMP-13

Cited by 216 publications

References 43 publications

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C 82 (OH) 22 and its implication for de novo design of nanomedicine

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C 82 (OH) 22 and its implication for de novo design of nanomedicine

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

Matrix metalloproteinase 13 is a new contributor to skeletal muscle regeneration and critical for myoblast migration

Contact Info

Product

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Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C ₈₂ (OH) ₂₂ and its implication for de novo design of nanomedicine