Kinase Degraders, Activators, and Inhibitors: Highlights and Synthesis Routes to the Chemical Probes on opnMe.com, Part 1.

Kinases are among the most important and successful drug targets. Chemical probe compounds have played a critical role in elucidating the role of kinases in many biological pathways. There are currently twelve well-validated chemical probes that target kinases available free-of-cost via the Molecules to Order (M2O) arm of Boehringer Ingelheim's open innovation platform, opnMe.

The influence of reward in the Simon task: Differences and similarities to the Stroop and Eriksen flanker tasks.

Previous studies have suggested that performance-contingent reward can modulate cognitive control by biasing irrelevant location-response associations in the Simon task. However, the influence of reward in the case of irrelevant words (Stroop task) or irrelevant flankers (Eriksen Flanker task) remains unclear. Across two preregistered experiments, the present study investigated the influence of reward on conflict processing with different types of distractors.

Application of leaf analysis in addition to growth assessment to evaluate the suitability of greywater for irrigation of Tilia cordata and Acer pseudoplatanus.

Water is the key resource in fulfilling the cooling function of plants in urban environments and needs to be supplied reliably and adequately, especially during dry periods. To avoid an unsustainable use of high-quality drinking water for irrigation, the reuse of greywater should be implemented for Green Infrastructure irrigation in the sense of the circular economy. In this study, the influence of greywater irrigation on vitality of two trees species, Tilia cordata and Acer pseudoplatanus, was determined by investigating the effect of irrigation with raw or treated greywater in comparison to municipal tap water.

Lipid A Mimetics Based on Unnatural Disaccharide Scaffold as Potent TLR4 Agonists for Prospective Immunotherapeutics and Adjuvants.

TLR4 is a key pattern recognition receptor that can sense pathogen- and danger- associated molecular patterns to activate the downstream signaling pathways which results in the upregulation of transcription factors and expression of interferons and cytokines to mediate protective pro-inflammatory responses involved in immune defense. Bacterial lipid A is the primary TLR4 ligand with very complex, species-specific, and barely predictable structure-activity relationships. Given that therapeutic targeting of TLR4 is an emerging tool for management of a variety of human diseases, the development of novel TLR4 activating biomolecules other than lipid A is of vast importance.

Intracellular Trapping of the Selective Phosphoglycerate Dehydrogenase (PHGDH) Inhibitor Disrupts Serine Biosynthesis.

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of , a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD)-competitive PHGDH inhibitor , which has shown high selectivity against the majority of other dehydrogenase targets.

Protective effects of an anti-melanocortin-4 receptor scFv derivative in lipopolysaccharide-induced cachexia in rats.

Background: Cachexia is a complex syndrome defined by weight loss due to an ongoing loss of skeletal muscle mass with or without loss of body fat. It is often associated with anorexia. Numerous results from experimental studies suggest that blockade of the melanocortin-4 receptor (MC4R) could be an effective treatment for anorexia and cachexia.

Metatropic dysplasia in four-year-old boy--physiotherapy and orthopaedic care problems--case report.

Metatropic dysplasia is a rare skeletal dysplasia caused by a mutation in the VDRL4 gene. Characteristic abnormalities include tubular bones with short diaphyses and wide metaphyses, delayed ossification of the ischio/pubic bone, and platyspondyly. The main problem is progressive kyphoscoliosis, which significantly limits the patient's motor development.

Antibodies raised against different extracellular loops of the melanocortin-3 receptor affect energy balance and autonomic function in rats.

Melanocortin receptors (MCR) play an important role in the regulation of energy balance and autonomic function. In the present studies, we used active immunization against peptide sequences from the first and the third extracellular loop (EL1 and EL3) of the MC3R to generate selective antibodies (Abs) against this MCR subtype in rats. Immunization with the EL1 peptide resulted in Abs that enhanced the effects of the endogenous ligand α-melanocyte-stimulating hormone (α-MSH), whereas immunization with the EL3 peptide resulted in Abs acting as non-competitive antagonists.

A pharmacologically active monoclonal antibody against the human melanocortin-4 receptor: effectiveness after peripheral and central administration.

The hypothalamic melanocortin-4 receptor (MC4R) is a constituent of an important pathway regulating food intake and energy expenditure. We produced a monoclonal antibody (mAb) directed against the N-terminal domain of the MC4R and evaluated its potential as a possible therapeutic agent. This mAb (1E8a) showed specific binding to the MC4R in human embryonic kidney 293 cells expressing the human MC4R and blocked the activity of the MC4R under basal conditions and after stimulation with alpha-melanocyte-stimulating hormone (alpha-MSH).

Placebo: misunderstandings and prejudices.

Background: The role of placebos is often misunderstood, leading both to overvaluation and to inappropriate disdain. The effect of a placebo that contains no pharmacologically active substance is often confused with the effect of administration by a physician. The aim of this article is to review the current data on placebos, evaluate these data critically, and provide a well-founded and understandable explanation of the effects that placebos do and do not possess.

Anti-melanocortin-4 receptor autoantibodies in obesity.

Background: The melanocortin-4 receptor (MC4R) is part of an important pathway regulating energy balance. Here we report the existence of autoantibodies (autoAbs) against the MC4R in sera of obese patients.

Methods: The autoAbs were detected after screening of 216 patients' sera by using direct and inhibition ELISA with an N-terminal sequence of the MC4R.

Antibodies as pharmacologic tools for studies on the regulation of energy balance.

Objective: Active immunization in rats may serve several purposes: the production of a disease-like phenotype, the generation of pharmacologic tools, and the development of clinically useful therapies. We selected the melanocortin-4 receptor (MC4R) as a target because its blockade could provide a treatment for anorexia and cachexia.

Methods: We used a sequence of the N-terminal (NT) domain of the MC4R as an antigen.

Functional chimeras of the phosphodiesterase 5 and 10 tandem GAF domains.

The tandem GAF domain of hPDE10A uses cAMP as an allosteric ligand (Gross-Langenhoff, M., Hofbauer, K., Weber, J.

Synthesis and identification of hydroxylated metabolites of the anti-estrogenic agent cyclofenil.

The detection of metabolites of the anti-estrogenic substance cyclofenil, listed on the World Anti-Doping Agency (WADA) Prohibited List since 2004 is described. Target substances are hydroxylated metabolites, bearing an aliphatic hydroxyl group either in the 2-, 3- or 4-position of the aliphatic ring, in addition to the phenolic functions on the aromatic rings. Structural identification used NMR as well as high-resolution mass spectrometry after nano-electrospray ionisation (ESI).

Academic institutions and industry: bridging the gap.

Academic institutions and industry are separate entities but strongly depend on each other. As innovation is their common interest, the exchange of scientific information and of highly qualified scientists is essential for their success. However, there are serious obstacles for the mobility of scientists between academic institutions and industry.

Melanocortin-4 receptor activation stimulates hypothalamic brain-derived neurotrophic factor release to regulate food intake, body temperature and cardiovascular function.

In the present study, we aimed to investigate the neuromodulatory role played by hypothalamic brain-derived neurotrophic factor (BDNF) in the regulation of acute cardiovascular and feeding responses to melanocortin-4 receptor (MC4R) activation. In vitro, a selective MC4R agonist, MK1, stimulated BDNF release from isolated rat hypothalami and this effect was blocked by preincubation with the MC3/4R antagonist SHU-9119. In vivo, peripheral administration of MK1 decreased food intake in rats and this effect was blocked by pretreatment with an anti-BDNF antibody administered into the third ventricle.

Antibodies against the melanocortin-4 receptor act as inverse agonists in vitro and in vivo.

Functionally active antibodies (Abs) against central G-protein-coupled receptors have not yet been reported. We selected the hypothalamic melanocortin-4 receptor (MC4-R) as a target because of its crucial role in the regulation of energy homeostasis. A 15 amino acid sequence of the N-terminal (NT) domain was used as an antigen.

Macrophage migration inhibitory factor (MIF) -173G/C promoter polymorphism influences upper gastrointestinal tract involvement and disease activity in patients with Crohn's disease.

Background: Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with increased expression in inflammatory bowel disease. The aim of the study was to analyze the role of the MIF -173G/C single nucleotide polymorphism in Crohn's disease (CD).

Methods: Using restriction fragment length polymorphism analysis, genomic DNA of 198 patients with CD and 159 unrelated controls was analyzed for the -173G/C SNP in the MIF promoter region.

Pharmacotherapy of obesity.

Obesity has become a significant health problem in industrialised and developing countries, and despite all nutritional and behavioural approaches, its prevalence is still increasing. In recent years, the identification and characterisation of central and peripheral mechanisms involved in the regulation of energy balance has made remarkable progress and provided numerous targets for novel anti-obesity agents. However, only few anti-obesity drugs are on the market and not many compounds have entered clinical development.

Homozygosity for the CARD15 frameshift mutation 1007fs is predictive of early onset of Crohn's disease with ileal stenosis, entero-enteral fistulas, and frequent need for surgical intervention with high risk of re-stenosis.

Objective: The identification of CARD15 as a susceptibility gene for Crohn's disease (CD) offers new possibilities for patient classification and risk assessment. The purpose of this study was to carry out a CARD15 sequence analysis in a large single-center IBD cohort and to investigate the impact of different genotypes on disease phenotypes.

Material And Methods: A total of 445 unrelated patients with IBD (68.

The obesity epidemic: current and future pharmacological treatments.

The unabated rise in the prevalence of obesity is a challenge for global health care systems. Efforts to reverse this trend by dietary or behavioral counseling have not been successful, which has stimulated efforts to find a role for pharmacotherapy. Currently only a small number of antiobesity drugs are approved for long-term use and only a few compounds are in clinical development.

Eight novel CARD15 variants detected by DNA sequence analysis of the CARD15 gene in 111 patients with inflammatory bowel disease.

We performed a limited DNA sequence analysis of the CARD15 gene in 89 patients with Crohn's disease (CD), 19 patients with ulcerative colitis (UC), and three patients with indeterminate colitis (IC), who were heterozygous carriers of one of the common CARD15 mutations [c.2104C>T (p.R702W), c.

Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice.

Cachexia affects many different chronically ill patient populations, including those with cancer. It results in loss of body weight, particularly of lean body mass (LBM), and is estimated to be responsible for over 20% of all cancer-related deaths. Currently, available drugs are ineffective, and new therapies are urgently needed.

Increased expression of the chemokine fractalkine in Crohn's disease and association of the fractalkine receptor T280M polymorphism with a fibrostenosing disease Phenotype.

Background: The fractalkine receptor CX3CR1 has been shown to be involved in inflammation and immune response. Recently, two polymorphisms of CX3CR1 (V249I and T280M) were reported.

Aims: Our aim was to analyze fractalkine expression and the role of CX3CR1 polymorphisms in Crohn's disease (CD).