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Heidelberg, Germany

Drewes G.,CellZome
Methods in Molecular Biology | Year: 2012

Real-world drug discovery and development remains a notoriously unproductive and increasingly uneconomical process even in the Omics era. The dominating paradigm in the industry continues to be target-based drug design, with an increased perception of the role of signaling pathways in homeostasis and in disease. Since proteins represent the major type of drug targets, proteomics-based approaches, which study proteins under relatively physiological conditions, have great potential if they can be reduced to practice such that they successfully complement the arsenal of drug discovery techniques. This chapter discusses examples of drug discovery processes where chemical proteomics-based assays using native endogenous proteins should have substantial impact. © 2012 Springer Science+Business Media, LLC. Source

Poeckel D.,Queens University | Poeckel D.,CellZome | Funk C.D.,Queens University
Cardiovascular Research | Year: 2010

Leukotrienes (LTs) derived from 5-lipoxygenase (5-LO) activity are most widely known for their actions during acute inflammation and asthma. 5-LO/LT pathway involvement in cardiovascular disease (CVD) pathogenesis has come to the forefront based on provocative human genetic/population and animal studies leading to the hypothesis that this pathway promotes atherosclerosis, abdominal aortic aneurysm, and myocardial infarction/reperfusion injury via increased leucocyte chemotaxis, vascular inflammation and enhanced permeability, and subsequent tissue/matrix degeneration. A series of pre-clinical studies have tested this hypothesis by means of genetic or pharmacological inhibition of either the LT biosynthesis axis (5-LO, 5-LO-activating protein, LTA4 hydrolase, LTC4 synthase) or the cognate LT receptors. Here, we summarize, compare, and analyse these animal studies and relate their findings to human disease pathogenesis. We draw a complex picture of 5-LO/LT participation in cardiovascular disorders, which is further complicated by marked differences between species. Moreover, we discuss how the cytokine footprint of the respective pathological conditions determines the expression level and hence, the contribution of components of the pathway to the overall disease state. Current knowledge implies a role for 5-LO and LTs during the early/acute phase of CVD, but our understanding of a putative 5-LO/LT involvement in more advanced stages of CVD is limited, thereby preventing simple extrapolation of findings from animal studies to humans. © The Author 2009. For permissions please. Source

Gantke T.,UK National Institute for Medical Research | Sriskantharajah S.,UK National Institute for Medical Research | Sriskantharajah S.,CellZome | Sadowski M.,UK National Institute for Medical Research | Ley S.C.,UK National Institute for Medical Research
Immunological Reviews | Year: 2012

Nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) activation play central roles in the induction of gene expression in innate immune cells following pathogen recognition. TPL-2 (tumor progression locus 2) is the MAP 3-kinase component of an ERK-1/2 (extracellular signal-regulated kinase 1/2) MAPK pathway activated by Toll-like receptor and tumor necrosis factor receptor family stimulation. In this review, we discuss results obtained from our laboratory and others that show that TPL-2 signaling function is directly controlled by the inhibitor of NF-κB (IκB) kinase (IKK) complex. Significantly, this means that IKK controls both NF-κB and ERK activation. TPL-2 is stoichiometrically complexed with the NF-κB inhibitory protein, NF-κB1 p105, and the ubiquitin-binding protein ABIN-2, both of which are required to maintain TPL-2 protein stability. Binding to p105 also prevents TPL-2 from phosphorylating MEK (MAPK/ERK kinase), its downstream target. Agonist stimulation releases TPL-2 from p105-inhibition by IKK-mediated phosphorylation of p105, which triggers degradation of p105 by the proteasome. This facilitates TPL-2 phosphorylation of MEK, in addition to liberating p105-associated Rel subunits to translocate into the nucleus. We also examine evidence that TPL-2 is critical for the induction of inflammation and may play a role in development and/or progression of certain types of cancer. Finally, we consider the potential of TPL-2 as an anti-inflammatory drug target for treatment of certain types of inflammatory disease and cancer. © 2012 John Wiley & Sons A/S. Source

The present invention is concerned with substituted bicyclic heterocyclic compounds of Formula (I) wherein Het

The present invention is concerned with novel substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione derivatives of Formula (I) wherein R

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