Recent advances in MMP inhibitor design

Fisher, Jed F.; Mobashery, Shahriar

doi:10.1007/s10555-006-7894-9

Cited by 239 publications

(209 citation statements)

References 217 publications

(217 reference statements)

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“…Anti-angiogenesis and blockers of enzymes involved in cancer cell-matrix interactions are currently under clinical investigation 97,98 with important benefits already obtained in randomised trials. 99 The tumor-associated fibroblast, has only recently became the focus of attention as an eventual anti-neoplasic therapeutic target.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

The pathology of tumor stromatogenesis

Giatromanolaki¹,

Sivridis²,

Koukourakis³

2007

Cancer Biology & Therapy

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Stromatogenesis is the formation of new, specific type, stroma at sites of active tumor cell invasion as an integral part of the invading process. The newly formed stroma by being wedged between tissue planes of least resistance disrupts the continuity of normal structures cleaving paths for the invading tumor cells-intramural stromatogenesis for endophytic tumors. Less frequently, the new stroma is formed towards a void space, i.e., at the free surfaces, whether internal or external (extramural stromatogenesis for exophytic tumors). It is postulated that the formation of this new stroma is generated and governed by the invading tumor cells with the tolerance and complicity of the adjacent activated fibroblasts. The spindle cells of the "neostroma" are intensely proliferating myofibroblasts, which are characterized by the frequent expression of a-smooth muscle actin and the particularly frequent expression of thymidine phosphorylase, PDGF-receptors and SPARC (secreted protein acidic rich in cysteine). The cellular and extracellular qualities, different as they are from those of reactive fibrosis, make stromatogenesis amenable to easy penetration by neoplastic cells and a prospective method for diagnosing early tumor invasion. Studies also suggest that the neostroma has complementary to cancer cell metabolic activity, important for buffering of cancer cell waste products and for the prevention of cancer cell acidic death. Thus, cancer cells and neostroma should not be seen as a mixture of heterogeneous uncoordinated cells but rather as a unified morphologic and metabolic domain with a harmonious collaboration between aerobic (myofibroblasts, endothelial cells) and anaerobic compartments (cancer cells).

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Section: Therapeutic Implicationsmentioning

confidence: 99%

The pathology of tumor stromatogenesis

Giatromanolaki¹,

Sivridis²,

Koukourakis³

2007

Cancer Biology & Therapy

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“…One obstacle to experimentally address distinct functions of gelatinases in vivo is that their structural similarity in the vicinity of the active center impedes the design of synthetic inhibitors targeting specifically only one gelatinase (20,21).…”

Section: Introductionmentioning

confidence: 99%

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Gerg

Kopitz²,

Schaten³

et al. 2008

Molecular Cancer Research

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The specific spatiotemporal role of the matrix metalloproteinase 2 (MMP-2) and MMP-9 (gelatinase) during metastasis is still under debate. Host cells have been described as major contributors to these MMPs during metastasis. Here, we show strong overexpression of MMP-2 and MMP-9 by tumor cells of clinical liver specimen of recurrent metachronous metastases, leading us to address the importance of tumor cell -derived MMP-2 or MMP-9 during liver metastasis. Thus far, distinction of their roles was impossible due to lack of inhibitors which can act exclusively on tumor cells or distinguish MMP-2 from MMP-9. We therefore used short hairpin RNA interference technology in the well-established syngeneic L-CI.5s lymphoma model, in which we could analyze the time course of experimental liver colonization (arrest/invasion of single tumor cells, outgrowth, and invasion within the parenchyma) in immunocompetent mice and correlate these steps with MMP-2 or MMP-9 expression levels. In parental tumor cells, MMP-9 expression closely correlated with the invasive phases of liver colonization, whereas MMP-2 expression remained unaltered. Specific knockdown of MMP-9 revealed a close correlation between invasion-dependent events and tumor cell -derived MMP-9 expression. In contrast, knockdown of MMP-2 did not significantly alter the metastatic potential of the cells but led to a marked inhibition of metastatic foci growth. These findings explain the efficacy of gelatinase-specific synthetic inhibitors on invasion and growth of tumor cells and attribute distinct functions of MMP-2 and MMP-9 to aspects of liver metastasis. (Mol Cancer Res 2008;6(3):341 -51)

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“…Through this effort we identified compound 2, a tetrahydropyran-based hydroxamate, which is a derivative of a known inhibitor (RS-130830) of matrix metalloprotease (MMP)-2, -8, -9, and -13. 19 Tetrahydropyran-based compound 2 demonstrated potent inhibition of P. aeruginosa LpxC (7.4 nM, Table 1), moderate cellular activity against P. aeruginosa PAO1 (MIC = 50 μM), but poor activity against wild-type Escherichia coli (E. coli ARC523 MIC >200 μM). We were attracted to the tetrahydropyran since this structural motif had not been employed in other LpxC inhibitors, yet it has similarity when compared to the natural substrate, UDP-3-O-(acyl)-N-acetylglucosamine.…”

mentioning

confidence: 99%

Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors

Murphy-Benenato

Olivier

Choy

et al. 2014

ACS Med. Chem. Lett.

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In the search for novel Gram-negative agents, we performed a comprehensive search of the AstraZeneca collection and identified a tetrahydropyran-based matrix metalloprotease (MMP) inhibitor that demonstrated nanomolar inhibition of UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC). Crystallographic studies in Aquifex aeolicus LpxC indicated the tetrahydropyran engaged in the same hydrogen bonds and van der Waals interactions as other known inhibitors. Systematic optimization of three locales on the scaffold provided compounds with improved Gram-negative activity. However, the optimization of LpxC activity was not accompanied by reduced inhibition of MMPs. Comparison of the crystal structure of the native product, UDP-3-O-(acyl)-glucosamine, in Aquifex aeolicus to the structure of a tetrahydropyran-based inhibitor indicates pathways for future optimization.KEYWORDS: Antibacterial, LpxC, Gram-negative bacteria, MMP, hydrophobe, Pseudomonas aeruginosa, Aquifex aeolicus T he need for new antibacterials active against Gram-negative bacteria is becoming critical. Current therapies are becoming ineffective due to increasing resistance, leaving healthcare practicioners with limited treatment options for serious bacterial infections. 1−3 To compound the issue, the presence of an additional cell membrane, incorporating lipopolysaccharide (LPS) in the outer leaflet, confers an intrinsic degree of resistance to Gram-negative pathogens. 4−6 The presence of the LPS layer, in addition to promiscuous efflux pumps, prevents agents effective at killing Gram-positive bacteria from penetrating the Gram-negative cellular envelope.UDP-3-O-(acyl)-N-acetylglucosamine deacetylase (LpxC) has become the focus of a number of programs aimed at the development of novel Gram-negative agents. 7 LpxC is a cytosolic zinc metallo-enzyme that catalyzes the deacetylation of UDP-3-O-(acyl)-N-acetylglucosamine, the first nonreversible step in the biosynthesis of lipid A, the main component and the substrate to which LPS is attached in the outer membrane of most Gramnegative bacteria. 8,9 Because the biosynthesis of lipid A is essential for maintenance of the outer membrane, LpxC is an attractive target for the development of new agents.A number of inhibitors of LpxC have been reported in the literature. 10−15 One of the most well documented inhibitors is CHIR-090 (1, Figure 1). 16−18 Key structural features of CHIR-090, which are consistent in other reported inhibitors, are a zincbinding group (hydroxamate) and a hydrophobic tail (hydrophobe), which sits in a narrow hydrophobic tunnel, usually occupied by the fatty acid tail of the natural substrate. The major difference between the various classes of inhibitors is the core that links the hydroxamate to the hydrophobe. CHIR-090 contains a threonine-based core, which has been shown to engage in a key hydrogen bond with Lys238 in Pseudomonas aeruginosa (P. aeruginosa) LpxC. Pfizer has reported on a series of methylsulfone-based inhibitors, which also take advantage of this hydrogen bon...

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Recent advances in MMP inhibitor design

Cited by 239 publications

References 217 publications

The pathology of tumor stromatogenesis

The pathology of tumor stromatogenesis

Distinct Functionality of Tumor Cell–Derived Gelatinases during Formation of Liver Metastases

Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors

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