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Lovejoy, Brett; Welch, Anthony; Carr, S.B.; Luong, Christine; Broka, Chris A.; Hendricks, R.; Campbell, J.A.; Walker, K.; Martin, Robert L.; Wart, H Van; Browner, Michelle F.

doi:10.1038/6657

Cited by 227 publications

(24 citation statements)

References 26 publications

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“…MMP13 lends itself to specific inhibition due to a relatively deep S1′ pocket [25]. Computational modeling has led to the identification of a panel of pyrimidinetrione-based inhibitors that are selective for MMP13 due to their binding in its deep S1′ pocket [26], [27].…”

Section: Introductionmentioning

confidence: 99%

An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer

et al. 2012

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We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.

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Section: Introductionmentioning

confidence: 99%

An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer

et al. 2012

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“…Matrix metalloproteinase (MMP)-1, commonly known as interstitial collagenase, is able to cleave interstitial collagens [1]. It belongs to a superfamily of zinc-dependent endopeptidases that are capable of degrading extracellular matrix components [2].…”

Section: Introductionmentioning

confidence: 99%

The Role of p300 Histone Acetyltransferase in UV-Induced Histone Modifications and MMP-1 Gene Transcription

et al. 2009

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Matrix metalloproteinase (MMP)-1 promotes ultraviolet (UV)-triggered long-term detrimental effects such as cancer formation and premature skin aging. Although histone modifications may play a crucial role in the transcriptional regulation of MMP-1, the relationship between UV-induced histone modification and MMP-1 expression is not completely understood. Here, we identify regulators of histone acetylation that may link UV-mediated DNA damage and MMP-1 induction by UV in cultured human dermal fibroblasts (HDFs) in vitro. UV irradiation of HDFs induced MMP-1 expression and increased the level of phosphorylation of H2AX (γ-H2AX), p53 and the acetylation of histone H3 (acetyl-H3). Total histone deacetylase (HDAC) enzymatic activity was decreased by UV irradiation, while histone acetyltransferase (HAT) activity was increased. Suppression of p300 histone acetyltransferase (p300HAT) activity by the p300HAT inhibitor anacardic acid (AA) or by down-regulation of p300 by siRNA prevented UV-induced MMP-1 expression and inhibited UV-enhanced γ-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that γ-H2AX, p53, acetyl-H3, p300 and c-Jun were consistently recruited by UV to a distinct region (−2067/−1768) adjacent to the p300 binding site (−1858/−1845) in the MMP-1 promoter. In addition, these recruitments of γ-H2AX, p53, acetyl-H3, p300 and c-Jun to the p300-2 site were significantly abrogated by post-treatment with AA. Furthermore, overexpression of p300 increased the basal and UV-induced MMP-1 promoter activity. Our results suggest that p300HAT plays a critical role in the transcriptional regulation of MMP-1 by UV.

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“…The same model has also been used to select potent molecules from 10,000 library molecules designed using Scaffold Hoping (Knowledge based screening). Library molecules were generated based on the knowledge of binding interaction of known ligands reported with MMP-1, MMP-8 & MMP-13 and also the common features necessary for biological activity of molecule [24–26]. These molecules were built using Cerius2 software [27] and conformations for each compound were generated using best conformational analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Differences in the relative size and shape of the S1' pockets in MMP-1, MMP-8 and MMP-13 suggest that this pocket is a critical determinant of MMP inhibitor selectivity [1]. The quite flexible loop forms a major portion of the S1' pocket and it undergoes a conformational change on inhibitor binding [14, 15]. The loop is of the same length in MMP-8 and MMP-13 and two residues are shorter in MMP-1[16].…”

Section: Introductionmentioning

confidence: 99%

Lead identification and optimization of novel collagenase inhibitors; pharmacophore and structure based studies

Kalva¹,

Vadivelan²,

Sanam³

et al. 2012

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In this study, chemical feature based pharmacophore models of MMP-1, MMP-8 and MMP-13 inhibitors have been developed with the aid of HypoGen module within Catalyst program package. In MMP-1 and MMP-13, all the compounds in the training set mapped HBA and RA, while in MMP-8, the training set mapped HBA and HY. These features revealed responsibility for the high molecular bioactivity, and this is further used as a three dimensional query to screen the knowledge based designed molecules. These pharmacophore models for collagenases picked up some potent and novel inhibitors. Subsequently, docking studies were performed for the potent molecules and novel hits were suggested for further studies based on the docking score and active site interactions in MMP-1, MMP-8 and MMP-13.

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Cited by 227 publications

References 26 publications

An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer

An MMP13-Selective Inhibitor Delays Primary Tumor Growth and the Onset of Tumor-Associated Osteolytic Lesions in Experimental Models of Breast Cancer

The Role of p300 Histone Acetyltransferase in UV-Induced Histone Modifications and MMP-1 Gene Transcription

Lead identification and optimization of novel collagenase inhibitors; pharmacophore and structure based studies

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