A5039022443- Protein Kinase Regulation and GTPase Signaling
- Chronic Lymphocytic Leukemia Research
- Cell Adhesion Molecules Research
- Pharmacogenetics and Drug Metabolism
- PI3K/AKT/mTOR signaling in cancer
- Cellular transport and secretion
- Chronic Myeloid Leukemia Treatments
- Renal Diseases and Glomerulopathies
- Complement system in diseases
- Monoclonal and Polyclonal Antibodies Research
- Platelet Disorders and Treatments
- Drug-Induced Hepatotoxicity and Protection
- Drug Transport and Resistance Mechanisms
- Cellular Mechanics and Interactions
- Phagocytosis and Immune Regulation
- Calcium signaling and nucleotide metabolism
- Biochemical Analysis and Sensing Techniques
- Acute Kidney Injury Research
- Blood groups and transfusion
- Immunodeficiency and Autoimmune Disorders
- Chronic Kidney Disease and Diabetes
- Pharmaceutical studies and practices
- Proteoglycans and glycosaminoglycans research
- Blood Pressure and Hypertension Studies
- Inflammatory mediators and NSAID effects
Novartis Institutes for BioMedical Research
2010-2022
Novartis (Switzerland)
2010-2022
Novartis (France)
2020
Ludwig Cancer Research
1992-1993
University College London
1993
Mount Sinai Hospital
1992
Lunenfeld-Tanenbaum Research Institute
1992
University of Basel
1989-1991
The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains. p85 alpha regulatory subunit phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-tyrosine kinases, also contains two SH2 Both domains, when expressed individually fusion in bacteria, bound stably the activated beta for platelet-derived...
A novel series of alkoxyimino derivatives as S1P1 agonists were discovered through de novo design using FTY720 the chemical starting point. Extensive structure-activity relationship studies led to discovery (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzyl)azetidine-3-carboxylic acid (32, BAF312, Siponimod), which has recently completed phase 2 clinical trials in patients with relapsing-remitting multiple sclerosis.
Abstract Safe and effective new oral therapies for autoimmune, allergic, inflammatory conditions remain a significant therapeutic need. Here, we investigate the human pharmacokinetics, pharmacodynamics (PDs), safety of selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor, remibrutinib. Study objectives were explored in randomized single multiple ascending dose (SAD MAD, respectively) cohorts with daily doses up to 600 mg, crossover food effect (FE) cohort, adult healthy subjects...
The interaction between SH2 domains and phosphotyrosine-containing sequences was examined by real-time measurements of kinetic parameters. the p85 subunit phosphatidylinositol 3-kinase as well other signaling molecules were expressed in bacteria glutathione S-transferase fusion proteins. Phosphotyrosine-containing peptides, corresponding to two autophosphorylation sites on human platelet-derived growth factor beta-receptor that are responsible for binding, synthesized used capturing...
Aliskiren (2(<i>S</i>),4(<i>S</i>),5(<i>S</i>),7(<i>S</i>)-<i>N</i>-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for treatment hypertension. The absorption, distribution, metabolism, and excretion [<sup>14</sup>C]aliskiren were investigated four healthy male subjects after administration single 300-mg oral dose an...
The large, multidomain extracellular matrix protein tenascin displays a markedly restricted tissue distribution during embryogenesis and remains present only in few adult tissues. is re‐expressed, however, wound healing the stroma of malignant tumours. While variety studies have dealt with important role development neural non‐neural tissues, there growing evidence that expression may be associated proliferation cells lining these presence repeating domains similar to those epidermal growth...
Phosphatidylinositol 3-kinase, which generates putative novel second messenger phospholipids, is a heterodimer composed of regulatory adaptor 85-kDa and catalytic 110-kDa subunits.The p85a subunit contains NHz-terminal src homology (SH) 3 domain, region with to the product breakpoint cluster (bcr) gene, COOH-terminal portion molecule two SH2 domains, separated by spacer region.In this study panel monoclonal antibodies (mAb) was raised against recombinant bovine probe its multidomain...
Fevipiprant is a novel oral prostaglandin D<sub>2</sub> receptor 2 (DP<sub>2</sub>; also known as CRTh2) antagonist, which currently in development for the treatment of severe asthma and atopic dermatitis. We investigated absorption, distribution, metabolism, excretion properties fevipiprant healthy subjects after single 200-mg dose [<sup>14</sup>C]-radiolabeled fevipiprant. metabolites were analyzed by liquid chromatography coupled to tandem mass spectrometry radioactivity measurements,...
Receptor-linked phosphatidylinositol (PtdIns) 3-kinase may generate a second-messenger signal. Here large-scale purification of the bovine brain enzyme, based on methods developed by Morgan, Smith and Parker [(1990) Eur. J. Biochem. 191, 761-767] Fry, Panayotou, Dhand, Ruiz-Larrea, Gout, Nguyen, Courtneidge Waterfield [(1992) 288, 383-393] is described. The purified enzyme shown to be heterodimer 85 kDa 110 protein subunits (p85 p110). Labelling with 5'-p-fluorosulphonylbenzoyladenosine...
The interaction between SH2 domains and phosphotyrosine-containing sequences was examined by real-time measurements of kinetic parameters. the p85 subunit phosphatidylinositol 3-kinase as well other signaling molecules were expressed in bacteria glutathione S-transferase fusion proteins. Phosphotyrosine-containing peptides, corresponding to two autophosphorylation sites on human platelet-derived growth factor beta-receptor that are responsible for binding, synthesized used capturing...
Pharmacokinetic drug-drug interactions (DDIs) are investigated to ensure safety for patients receiving concomitant medications. Here, we present a strategy characterise the DDI potential of remibrutinib, as an inhibitor drug-metabolising enzymes and drug transporters, inducer. Initial in vitro studies were performed, followed by biomarker-based assessment induction first human study, concluded clinical study verify initial results. Remibrutinib is covalent Bruton's Tyrosine kinase (BTKi)...
Abstract Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be predominant elimination pathway remibrutinib. The impact concomitant treatment with inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study combination an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including fraction absorbed, fractions...
Abstract Background and Aims The alternative complement pathway (AP) provides the central amplification loop of activation is critically involved in a number diseases including C3 glomerulopathy (C3G), paroxysmal nocturnal haemoglobinuria (PNH) atypical haemolytic uremic syndrome. There also evidence for AP dysregulation IgA membranous nephropathies (IgAN, MN). Novartis has developed highly selective oral low molecular weight inhibitor Factor B, key protease. LNP023 potently blocks vitro...
Introduction: Because of the importance to create in vitro screening tools that better mimic vivo models, for exposure responses drugs or toxicants, reproducible and adaptable culture platforms must evolve as approaches replicate functions are native human organ systems. The Stairstep Waterfall (SsWaterfall) Fluidic Culture System is a unidirectional, multiwell, gravity-driven, cell system with micro-channels connecting 12 wells each row (8-row replicates). Materials Methods: construct...