N-Hydroxyformamide peptidomimetics as TACE/Matrix metalloprotease inhibitors: oral activity via P1′ isobutyl substitution

Musso, David L.; Andersen, Marc W.; Andrews, Robert C.; Austin, Robert J.; Beaudet, Elizabeth J.; Becherer, J. David; Bubacz, Dulce G.; Bickett, D. Mark; Chan, Jason S.; Conway, James G.; Cowan, David J.; Gaul, Michael D.; Glennon, Kimberly; Hedeen, Kevin M.; Lambert, Millard H.; Leesnitzer, M. Anthony; McDougald, Darryl; Mitchell, Justin; Moss, Marcia L.; Rabinowitz, Michael H.; Rizzolio, Michèle; Schaller, Lee T.; Stanford, Jennifer B.; Tippin, Timothy K.; Warner, Janet; Whitesell, Luke; Wiethe, Robert W.

doi:10.1016/s0960-894x(01)00377-8

Cited by 21 publications

(7 citation statements)

References 19 publications

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“…TACE activity was measured using streptavidin-coated scintillation proximity assay (SPA) beads and a biotinylated peptide corresponding to the cleavage site in pro-TNF-␣ as described previously. 46,47 Assays were performed at room temperature with 200 nM substrate (biotin-SPLAQAVRSSSRTP( 3 H)S-NH 2 ) in 10 mM HEPES (N-2-hydroxyethylpiperazine-NЈ-2-ethanesulfonic acid) buffer, pH 7.5, containing 0.0015% Brij-35. Reactions were stopped by addition of streptavidin-SPA beads (Amersham, Freiburg, Germany) in EDTA (ethylenediaminetetraacetic acid) and uncleaved substrate measured by scintillation counting.…”

Section: Metalloproteinase Inhibitorsmentioning

confidence: 99%

The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion

Hundhausen

Misztela

Berkhout

et al. 2003

Blood

643

594

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The CX3C chemokine fractalkine (CX3CL1) exists as a membrane-expressed protein promoting cell-cell adhesion and as a soluble molecule inducing chemotaxis. Transmembrane CX3CL1 is converted into its soluble form by defined proteolytic cleavage (shedding), which can be enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA). PMA-induced CX3CL1 shedding has been shown to involve the tumor necrosis factor-␣-converting enzyme (TACE), whereas the constitutive cleavage in unstimulated cells remains elusive. Here we demonstrate a role of the closely related disintegrin-like metalloproteinase 10 (ADAM10) in the constitutive CX3CL1 cleavage. The hydroxamate GW280264X, capable of blocking TACE as well as ADAM10, proved to be an effective inhibitor of the constitutive and the PMA-inducible CX3CL1 cleavage in CX3CL1-expressing ECV-304 cells (CX3CL1-ECV-304), whereas GI254023X, preferentially blocking ADAM10 but not TACE, reduced the constitutive cleavage only. Overexpression of ADAM10 in COS-7 cells enhanced constitutive cleavage of CX3CL1 and, more importantly, in murine fibroblasts deficient of ADAM10 constitutive CX3CL1 cleavage was markedly reduced. Thus, ADAM10 contributes to the constitutive shedding of CX3CL1 in un- IntroductionLeukocyte recruitment to inflammatory sites involves a sequence of adhesive events that are mediated by different classes of adhesion molecules expressed on the endothelium and the leukocytes. 1 Whereas adhesion molecules of the selectin family usually contribute to the rolling of leukocytes under flow, members of the integrin family are involved in establishing a stable shear-resistant cell adhesion. Chemokines are thought to play a role in modulating cell adhesion by inducing shedding of L-selectin and by increasing functional integrins on the leukocyte surface. Thus, besides acting as chemoattractants in the tissue, chemokines can promote the transition from an early to a late adhesion type in the course of leukocyte recruitment.Within the chemokine family a transmembrane molecule termed CX3C chemokine ligand 1 (CX3CL1), or fractalkine, has been identified that by itself induces adhesion. 2 CX3CL1 is encoded as a 95-kDa multidomain molecule consisting of a chemokine domain linked to a transmembrane domain via a mucin-rich stalk. The chemokine is expressed on endothelial cells, 2 epithelial cells, 3,4 smooth muscle cells, 5,6 dendritic cells, 7,8 neurons, 9,10 and macrophages. 11 In vitro, CX3CL1 induces cell adhesion by interaction with its receptor CX3CR1 expressed on monocytes, T cells, mast cells, and natural killer cells. 2,[12][13][14] This adhesion does not require signaling of the receptor, is resistant to physiologic shear flow, and is independent of extracellular calcium. 2,15,16 Besides its activity as an adhesion molecule, CX3CL1 can be cleaved from the cell membrane to produce a soluble 80-kDa molecule that induces chemotaxis of CX3CR1-expressing leukocytes. 2 In vivo, upregulation of CX3CL1 has been found in atherosclerotic blood vessels, 6,11 rejected transplants, 1...

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Section: Metalloproteinase Inhibitorsmentioning

confidence: 99%

The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion

Hundhausen

Misztela

Berkhout

et al. 2003

Blood

643

594

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“…From other areas of investigation, for instance the matrix metallo-proteases [49], it is well known that the hydroxamate function exhibits a strong affinity to Zn 2þ and other metal ions and hence contributes significantly to the affinity of the ligands to their biological targets. Within the HDAC field, a large variety of hydroxamic acids have been studied aiming at therapeutic agents for oncology and other disease areas.…”

Section: Hydroxamic Acidsmentioning

confidence: 99%

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

Bürli¹,

Thomas²,

Beaumont

2010

Topics in Medicinal Chemistry

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Neurodegenerative disorders are devastating for patients and their social environment. Their etiology is poorly understood and complex. As a result, there is clearly an urgent need for therapeutic agents that slow down disease progress and alleviate symptoms. In this respect, interference with expression and function of multiple gene products at the epigenetic level has offered much promise, and histone deacetylases play a crucial role in these processes. This review presents an overview of the biological pathways in which these enzymes are involved and illustrates the complex network of proteins that governs their activity. An overview of small molecules that interfere with histone deacetylase function is provided.

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“…Earlier studies showing that MMP hydroxamate inhibitors also behave as potent TACE inhibitors led to the suggestion that the catalytic domains of TACE and MMPs have a similar topology (Le and Abbenante, 2005). Compound 8 with a reverse hydroxamate zinc-binding group is an example of such inhibitors (Scheme 3), which displays an IC 50 of 40 nM toward TACE and is also a potent blocker of several MMPs (IC 50 < 20 nM) (Musso et al, 2001). Thus, development of TACE inhibitors has evolved from MMP inhibitor design programs, a situation explaining the presence of the hydroxamate group in most TACE inhibitors.…”

Section: Adam Synthetic Inhibitorsmentioning

confidence: 99%

Synthetic active site-directed inhibitors of metzincins: Achievement and perspectives

Yiotakis

Dive

2008

Molecular Aspects of Medicine

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N-Hydroxyformamide peptidomimetics as TACE/Matrix metalloprotease inhibitors: oral activity via P1′ isobutyl substitution

Cited by 21 publications

References 19 publications

The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion

The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion

The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach

Synthetic active site-directed inhibitors of metzincins: Achievement and perspectives

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