A5008757426- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- PI3K/AKT/mTOR signaling in cancer
- Estrogen and related hormone effects
- Cytokine Signaling Pathways and Interactions
- NF-κB Signaling Pathways
- Immunodeficiency and Autoimmune Disorders
- Autoimmune Bullous Skin Diseases
- DNA Repair Mechanisms
- Hormonal Regulation and Hypertension
- Genetic factors in colorectal cancer
- Cancer Genomics and Diagnostics
- Mast cells and histamine
- Retinoids in leukemia and cellular processes
- Phytoestrogen effects and research
- Cell Adhesion Molecules Research
- Lymphoma Diagnosis and Treatment
- Folate and B Vitamins Research
- Monoclonal and Polyclonal Antibodies Research
- Urticaria and Related Conditions
- Multiple Sclerosis Research Studies
- Chemokine receptors and signaling
- Protein Degradation and Inhibitors
- Nuclear Receptors and Signaling
- Protein Hydrolysis and Bioactive Peptides
Novartis (Switzerland)
2008-2024
Novartis Institutes for BioMedical Research
2008-2024
Novartis (China)
2024
Novartis (France)
2020
University of Geneva
1999-2010
University Hospital of Bern
2001-2007
University of Bern
2003-2006
University of California, San Diego
1996-2001
Swiss Tropical and Public Health Institute
1995
Bruton's tyrosine kinase (BTK), a cytoplasmic kinase, plays central role in immunity and is considered an attractive target for treating autoimmune diseases. The use of currently marketed covalent BTK inhibitors limited to oncology indications based on their suboptimal selectivity. We describe the discovery preclinical profile LOU064 (remibrutinib, 25), potent, highly selective inhibitor. exhibits exquisite selectivity due binding inactive conformation has potential best-in-class inhibitor...
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 estrogen receptor α (ERα) is activated as a transcription factor by both and large variety of other extracellular signals. mechanisms this ligand-independent activation, notably cAMP signaling, are still largely unknown. We now close the gap in signaling pathway between ERα. Whereas direct phosphorylation ERα cAMP-activated protein kinase A (PKA) dispensable, coactivator-associated arginine methyltransferase 1 (CARM1) PKA at single serine necessary sufficient for binding to unliganded...
Despite advances in the treatment of chronic urticaria, a significant percentage patients symptoms are not fully controlled with conventional approaches. New strategies under development include blocking intracellular mediators mast cell and basophil activation.We aim to investigate effects Bruton's tyrosine kinase (BTK) inhibitor remibrutinib on human blood basophils CD34+ -derived cells activation induced by serum obtained from urticaria patients.Twenty-two spontaneous (mean age 52 years,...
Objectives To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren’s syndrome (SjS) a phase 2 randomised, double-blind trial ( NCT04035668 ; LOUiSSE (LOU064 Syndrome) study). Methods Eligible fulfilling 2016 American College Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive anti-Ro/Sjögren’s syndrome-related antigen A antibodies, disease activity (EULAR Syndrome Disease Activity Index (ESSDAI) (based on weighted score)...
Abstract Non-random gamete fusion is one of several potential cryptic female choice mechanisms that have been postulated and may enhance the survival probability offspring. Previous studies found in mice influenced by genes major histocompatibility complex (MHC) region. Here we test (i) whether there MHC-dependent whitefish (Coregonus sp.) (ii) a link between MHC embryo susceptibility to an infection bacterium Pseudomonas fluorescens. We experimentally bred reared sibships batches either...
Protease-activated receptor 2 (PAR-2) activation has been linked to pro- and antiinflammatory cellular responses. We undertook this study explore the importance of PAR-2 in 4 murine models arthritis analyze expression human arthritic synovium.Zymosan-induced (ZIA), K/BxN serum-induced arthritis, Freund's complete adjuvant (CFA)-induced were generated naive PAR-2(-/-) mice PAR-2(+/+) littermates. Antigen-induced (AIA) was immunized using methylated bovine serum albumin (mBSA). The severity...
The intracellular signaling pathway by which tumor necrosis factor (TNF) induces its pleiotropic actions is well characterized and includes unique components as modules shared with other pathways. In addition to the currently known key effectors, further molecules may however modulate biological response TNF. our attempt characterize novel regulators of TNF cascade, we have identified transmembrane protein 9B (TMEM9B, c11orf15) an important component a module interleukin 1β (IL-1β) Toll-like...
Significance During the last decades, heart failure has developed into a major burden in western world, increasingly affecting millions. Cardiac hypertrophy is an adaptive response to myocardial infarction or increased blood pressure, and it often leads failure. Understanding underlying regulatory processes development of pathological needed for effective therapies. Our results show that kinase activity endothelial bone marrow chromosome X (Bmx) protein necessary cardiac hypertrophy. This...
Insulin-like growth factor (IGF-1) is a potent mitogen for vascular smooth muscle cells. Both IGF-1 and its receptor have been shown to be highly expressed in atherosclerotic lesions. Here we investigated whether part of the vasculoprotective properties E<sub>2</sub> may mediated by negative regulation system. HeLa cells, which do not contain endogenous estrogen receptors (ER), were transiently transfected with IGF-1R promoter constructs or without plasmid encoding human ERα ERβ treated 100...
Reduced activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a role in essential hypertension and the sensitivity blood pressure to dietary salt. Nonconservative mutations coding region are extremely rare do not explain variable 11beta-HSD2 activity. We focused therefore on 5'-regulatory identified characterized first promoter polymorphisms. Transfections variants G-209A G-126A into SW620 cells reduced affinity for activators nuclear factor 1 (NF1) Sp1. Chromatin...
Inflammatory cytokines like TNF play a central role in autoimmune disorders such as rheumatoid arthritis. We identified the tyrosine kinase bone marrow on chromosome X (BMX) an essential component of shared inflammatory signaling pathway. Transient depletion BMX strongly reduced secretion IL-8 cell lines and primary human cells stimulated by TNF, IL-1β, or TLR agonists. was required for phosphorylation p38 MAPK JNK, well activation NF-κB. The following epistasis analysis indicated that acts...
Summary. One fifth of B‐cell chronic lymphocytic leukaemia (B‐CLL) patients exhibit loss heterozygosity (LOH) at 10q23.3, the site tumour suppressor PTEN. Microsatellite markers mapped complete LOH to 10q23.3 in 2/41 B‐CLL (5%) and allelic imbalances 6/41 (15%). No PTEN gene mutations were found. protein expression was not detected 11 (28%), reduced eight (20%). or fairly frequent B‐CLL, but did encompass gene. Nevertheless, may be absent with a normal genotype, suggesting role this...
1. The major serum proteins which bind halofantrine were identified by size exclusion chromatography. In addition, the binding affinity of to human erythrocytes and was measured an erythrocyte partitioning technique. influence serum‐drug on distribution in whole blood estimated simulating several disease‐related changes levels most important proteins. 2. chromatographic resolution preincubated with allowed a quantitative analysis low density lipoproteins, high alpha 1‐acid glycoprotein...
Bruton's tyrosine kinase (BTK) is a member of the TEC family and selectively expressed in subset immune cells. It key regulator antigen receptor signaling B cells Fc mast macrophages. A BTK inhibitor will likely have positive impact on autoimmune diseases which are caused by autoreactive immune-complex driven inflammation. We report design, optimization, characterization potent selective covalent inhibitors. Starting from reversible 3 binding to an inactive conformation BTK, we designed...
Abstract Background Bruton’s tyrosine kinase (BTK) is a key signaling node in B cell receptor (BCR) and Fc (FcR) signaling. BTK inhibitors (BTKi) are an emerging oral treatment option for patients suffering from multiple sclerosis (MS). Remibrutinib (LOU064) potent, highly selective covalent BTKi with promising preclinical clinical profile MS other autoimmune or autoallergic indications. Methods The efficacy mechanism of action remibrutinib was assessed two different experimental...
To assess the correlation of neurofilament light chain (NfL; potential biomarker for multiple sclerosis [MS] disease activity) in cerebrospinal fluid (CSF)/plasma an experimental autoimmune encephalomyelitis (EAE) mouse model.