An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
American Journal of Physiology-Lung Cellular and Molecular Physiology
Shifts in cellular metabolic phenotypes have the potential to cause disease-driving processes in ... more Shifts in cellular metabolic phenotypes have the potential to cause disease-driving processes in respiratory disease. The respiratory epithelium is particularly susceptible to metabolic shifts in disease, but our understanding of these processes is limited by the incompatibility of the technology required to measure metabolism in real-time with the cell culture platforms used to generate differentiated respiratory epithelial cell types. Thus, to date, our understanding of respiratory epithelial metabolism has been restricted to that of basal epithelial cells in submerged culture, or via indirect end point metabolomics readouts in lung tissue. Here we present a novel methodology using the widely available Seahorse Analyzer platform to monitor real-time changes in the cellular metabolism of fully differentiated primary human airway epithelial cells grown at air-liquid interface (ALI). We show increased glycolytic, but not mitochondrial, ATP production rates in response to physiologica...
In an effort to find new therapeutic interventions addressing the unmet medical need of patients ... more In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.
The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Pica... more The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Picato, a first-in-class treatment for the precancerous skin condition actinic keratosis. IngMeb is proposed to exert its therapeutic effects through a dual mode of action involving (i) induction of cell death that is associated with mitochondrial dysfunction followed by (ii) stimulation of a local inflammatory response, at least partially driven by protein kinase C (PKC) activation. Although this therapeutic model has been well characterized, the complete set of molecular targets responsible for mediating IngMeb activity remains ill-defined. Here, we have synthesized a photoreactive, clickable analogue of IngMeb and used this probe in quantitative proteomic experiments to map several protein targets of IngMeb in human cancer cell lines and primary human keratinocytes. Prominent among these targets was the mitochondrial carnitine-acylcarnitine translocase SLC25A20, which we show is inhibited...
Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate ... more Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear. The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injur...
Current Opinion in Drug Discovery Development, Nov 1, 2008
A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past... more A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past are presented. An overview of the most common fluorination reagents is followed by descriptions of fluorination reactions that are organized by reactivity. The distinction between nucleophilic and electrophilic fluorinations is highlighted, as well as between aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for the synthesis of pharmaceuticals, [18F]radiolabeling and mechanistic investigations are provided.
Current opinion in drug discovery & development, 2008
A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past... more A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past are presented. An overview of the most common fluorination reagents is followed by descriptions of fluorination reactions that are organized by reactivity. The distinction between nucleophilic and electrophilic fluorinations is highlighted, as well as between aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for the synthesis of pharmaceuticals, [18F]radiolabeling and mechanistic investigations are provided.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
American Journal of Physiology-Lung Cellular and Molecular Physiology
Shifts in cellular metabolic phenotypes have the potential to cause disease-driving processes in ... more Shifts in cellular metabolic phenotypes have the potential to cause disease-driving processes in respiratory disease. The respiratory epithelium is particularly susceptible to metabolic shifts in disease, but our understanding of these processes is limited by the incompatibility of the technology required to measure metabolism in real-time with the cell culture platforms used to generate differentiated respiratory epithelial cell types. Thus, to date, our understanding of respiratory epithelial metabolism has been restricted to that of basal epithelial cells in submerged culture, or via indirect end point metabolomics readouts in lung tissue. Here we present a novel methodology using the widely available Seahorse Analyzer platform to monitor real-time changes in the cellular metabolism of fully differentiated primary human airway epithelial cells grown at air-liquid interface (ALI). We show increased glycolytic, but not mitochondrial, ATP production rates in response to physiologica...
In an effort to find new therapeutic interventions addressing the unmet medical need of patients ... more In an effort to find new therapeutic interventions addressing the unmet medical need of patients with idiopathic pulmonary fibrosis, we initiated a program to identify new autotaxin (ATX) inhibitors. Starting from a recently published compound (PF-8380), we identified several highly potent ATX inhibitors with improved pharmacokinetic and safety profiles. Further optimization efforts resulted in the identification of a single-digit nanomolar lead compound (BI-2545) that shows substantial lowering of LPA in vivo and is therefore considered a valuable tool for further studies.
The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Pica... more The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Picato, a first-in-class treatment for the precancerous skin condition actinic keratosis. IngMeb is proposed to exert its therapeutic effects through a dual mode of action involving (i) induction of cell death that is associated with mitochondrial dysfunction followed by (ii) stimulation of a local inflammatory response, at least partially driven by protein kinase C (PKC) activation. Although this therapeutic model has been well characterized, the complete set of molecular targets responsible for mediating IngMeb activity remains ill-defined. Here, we have synthesized a photoreactive, clickable analogue of IngMeb and used this probe in quantitative proteomic experiments to map several protein targets of IngMeb in human cancer cell lines and primary human keratinocytes. Prominent among these targets was the mitochondrial carnitine-acylcarnitine translocase SLC25A20, which we show is inhibited...
Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate ... more Autotaxin (ATX) is a secreted phospholipase which hydrolyses lysophosphatidylcholine to generate lysophosphatidic acid (LPA). The extracellular signalling molecule LPA exerts its biological actions through activation of six GPCRs expressed in various cell types including fibroblasts. Multiple preclinical studies using knockout animals, LPA receptor antagonists or ATX inhibitors have provided evidence for a potential role of the ATX/LPA axis in tissue fibrosis. Despite growing evidence for a correlation between ATX levels and the degree of fibrosis in chronic liver diseases, including viral hepatitis and hepatocellular carcinoma, the role of ATX in non-alcoholic steatohepatitis (NASH) remains unclear. The relevance of ATX in the pathogenesis of liver fibrosis was investigated by oral administration of Ex_31, a selective ATX inhibitor, in a 10 week model of carbon tetrachloride-induced liver injury and in a 14 week model of choline-deficient amino acid-defined diet-induced liver injur...
Current Opinion in Drug Discovery Development, Nov 1, 2008
A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past... more A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past are presented. An overview of the most common fluorination reagents is followed by descriptions of fluorination reactions that are organized by reactivity. The distinction between nucleophilic and electrophilic fluorinations is highlighted, as well as between aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for the synthesis of pharmaceuticals, [18F]radiolabeling and mechanistic investigations are provided.
Current opinion in drug discovery & development, 2008
A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past... more A selection of carbon-fluorine bond-forming reactions that have been developed in the recent past are presented. An overview of the most common fluorination reagents is followed by descriptions of fluorination reactions that are organized by reactivity. The distinction between nucleophilic and electrophilic fluorinations is highlighted, as well as between aliphatic and aromatic fluorinations. Each section is divided into more specific reaction classes and examples for the synthesis of pharmaceuticals, [18F]radiolabeling and mechanistic investigations are provided.
Uploads
Papers by Christian Kuttruff