Insight into the structural determinants for selective inhibition of matrix metalloproteinases

Pirard, Bernard

doi:10.1016/j.drudis.2007.06.003

Cited by 92 publications

(72 citation statements)

References 32 publications

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“…S6). 8 The MMP gene family including MMP1 and MMP3 are also recognized as pharmaceutical targets (32). The challenge ahead for this class of drugs appears to be in the development of specific active sitedirected inhibitors against specific MMPs (32).…”

Section: Discussionmentioning

confidence: 99%

“…8 The MMP gene family including MMP1 and MMP3 are also recognized as pharmaceutical targets (32). The challenge ahead for this class of drugs appears to be in the development of specific active sitedirected inhibitors against specific MMPs (32). Although our analysis has confirmed the overexpression of these genes in many cancers, we have also identified several novel tumors that express MMP1 (chondroblastoma) and MMP3 (chordoma and seminoma), suggesting that the full range of malignancies that the drugs against these targets could be used for is yet to be explored ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

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Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets

Flanagan

Funes

Henderson

et al. 2009

Molecular Cancer Therapeutics

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Since the sequencing of the human genome, recent efforts in cancer drug target discovery have focused more on the identification of novel functions of known genes and the development of more appropriate tumor models. In the present study, we investigated in vitro transformed human adult mesenchymal stem cells (MSC) to identify novel candidate cancer drug targets by analyzing the transcriptional profile of known enzymes compared with non-transformed MSC. The identified enzymes were compared with published cancer gene expression data sets. Surprisingly, the majority of up-regulated enzymes are already known cancer drug targets or act within known druggable pathways. Only three enzymes (RNASEH2A, ADARB1, and PPAP2C) are potentially novel targets that are up-regulated in transformed MSC and expressed in numerous carcinomas and sarcomas. We confirmed the overexpression of RNASEH2A, PPAP2C, and ADARB1 in transformed MSC, transformed fibroblasts, and cancer cell lines MCF7, SK-LMS1, MG63, and U2OS. In functional assays, we show that small interfering RNA knockdown of RNASEH2A inhibits anchorage-independent growth but does not alter in vitro proliferation of cancer cell lines, normal MSC, or normal fibroblasts. Knockdown of PPAP2C impaired anchorage-dependent in vitro growth of cancer cell lines and impaired the in vitro growth of primary MSC but not differentiated human fibroblasts. We show that the knockdown of PPAP2C decreases cell proliferation by delaying entry into S phase of the cell cycle and is transcriptionally regulated by p53. These in vitro data validate PPAP2C and RNASEH2A as putative cancer targets and endorse this in silico approach for identifying novel candidates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets

Flanagan

Funes

Henderson

et al. 2009

Molecular Cancer Therapeutics

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“…The growing availability of MMP 3D structures has contributed to develop and speed up the drug design process, which can now exploit realistic molecular modeling procedures (Aureli et al, 2008;Pirard, 2007).…”

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confidence: 99%

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Sbardella

Fasciglione

Gioia

et al. 2012

Molecular Aspects of Medicine

205

212

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a b s t r a c tHuman matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn 2+ atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes.

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“…Because MMPs have not only disease promoting but also inhibiting functions (53, 54), a major challenge in current MMP inhibitor design is selectivity toward target MMPs (55,56). Our refined specificity profile discriminates MMP10 e.g.…”

Section: Discussionmentioning

confidence: 99%

Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions*

Schlage

Kockmann

Sabino

et al. 2015

Molecular & Cellular Proteomics

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Insight into the structural determinants for selective inhibition of matrix metalloproteinases

Cited by 92 publications

References 32 publications

Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets

Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Matrix Metalloproteinase 10 Degradomics in Keratinocytes and Epidermal Tissue Identifies Bioactive Substrates With Pleiotropic Functions*

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