A5085446151- Angiogenesis and VEGF in Cancer
- PI3K/AKT/mTOR signaling in cancer
- Vascular Tumors and Angiosarcomas
- Protein Kinase Regulation and GTPase Signaling
- Receptor Mechanisms and Signaling
- Cell Adhesion Molecules Research
- Asthma and respiratory diseases
- Lymphatic System and Diseases
- T-cell and B-cell Immunology
- Cytokine Signaling Pathways and Interactions
- Psoriasis: Treatment and Pathogenesis
- X-ray Diffraction in Crystallography
- HER2/EGFR in Cancer Research
- Immunotherapy and Immune Responses
- Mast cells and histamine
- Estrogen and related hormone effects
- Renal cell carcinoma treatment
- NF-κB Signaling Pathways
- Complement system in diseases
- Crystallization and Solubility Studies
- Whipple's Disease and Interleukins
- Chemical Synthesis and Analysis
- Autoimmune and Inflammatory Disorders
- Muscle Physiology and Disorders
- Monoclonal and Polyclonal Antibodies Research
Novartis Institutes for BioMedical Research
2010-2023
Novartis (Switzerland)
2011-2023
Institute of Cancer Research
2010
Royal Marsden Hospital
2010
Rockefeller University Press
2002
Rockefeller University
2002
University of Wisconsin–Madison
2001
San Raffaele University of Rome
2001
When SUCNR1/GPR91-expressing macrophages are activated by inflammatory signals, they change their metabolism and accumulate succinate. In this study, we show that during activation, release succinate into the extracellular milieu. They simultaneously up-regulate GPR91, which functions as an autocrine paracrine sensor for to enhance IL-1β production. GPR91-deficient mice lack metabolic reduced macrophage activation production of antigen-induced arthritis. Succinate is abundant in synovial...
Dysregulation of the alternative complement pathway (AP) predisposes individuals to a number diseases including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and C3 glomerulopathy. Moreover, glomerular Ig deposits can lead complement-driven nephropathies. Here we describe discovery highly potent, reversible, selective small-molecule inhibitor factor B, serine protease that drives central amplification loop AP. Oral administration prevents KRN-induced arthritis in...
Tumor necrosis factor (TNF) is a key driver of several inflammatory diseases, such as rheumatoid arthritis, bowel disease, and psoriasis, in which affected tissues show an interferon-stimulated gene signature. Here, we demonstrate that TNF triggers type-I interferon response dependent on the cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator genes (STING) pathway. We inhibits PINK1-mediated mitophagy leads to altered mitochondrial function increase cytosolic mtDNA levels. Using...
Abstract FTY720, a potent immunomodulator, becomes phosphorylated in vivo (FTY-P) and interacts with sphingosine-1-phosphate (S1P) receptors. Recent studies showed that FTY-P affects vascular endothelial growth factor (VEGF)–induced permeability, an important aspect of angiogenesis. We show here FTY720 has antiangiogenic activity, potently abrogating VEGF- S1P-induced angiogenesis implant corneal models. administration tended to inhibit primary significantly inhibited metastatic tumor mouse...
Comparison of the antiangiogenic/vascular properties oral mammalian target rapamycin (mTOR) inhibitor RAD001 (everolimus) and vascular endothelial growth factor receptor (VEGFR) vatalanib (PTK/ZK).Antiproliferative activity against various tumor histotypes downstream effects on mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, levels measured. Activity several different angiogenic/vascular assays vitro vivo was assessed compared with PTK/ZK.RAD001 inhibited...
Dysregulated angiogenesis and high tumor vasculature permeability, two vascular endothelial growth factor (VEGF)-mediated processes hallmarks of human tumors, are in part phosphatidylinositol 3-kinase (PI3K) dependent. NVP-BEZ235, a dual PI3K/mammalian target rapamycin (mTOR) inhibitor, was found to potently inhibit VEGF-induced cell proliferation survival vitro vivo as shown with s.c. VEGF-impregnated agar chambers. Moreover, the compound strongly inhibited microvessel permeability both...
Blood vessels comprise endothelial cells, mural cells (pericytes/vascular smooth muscle cells) and basement membrane. During angiogenesis, are recruited to sprouting define a stabilizing context, comprising cell-cell contacts, secreted growth factors extracellular matrix components, that drives vessel maturation resistance anti-angiogenic therapeutics.To better understand the basis for cell regulation of we conducted high content imaging analysis on microtiter plate format in vitro...
Abstract The mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti–IL-17 therapy in collagen-induced ameliorates bone damage by reducing the number of osteoclasts joints. found equal numbers CD4+ Th17 and producing γδ T cells joints arthritic mice, vitro, both populations similarly induced osteoclastogenesis. However, individual depletion adoptive transfer studies revealed vivo, dominated with regard to destruction. Unlike cells, were...
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...
The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role B T cell functions led to the hypothesis that selective inhibitors this isoform would have potential as therapeutics for treatment allergic inflammatory disease. Targeting specifically PI3Kδ should avoid side effects associated with ubiquitously expressed PI3Kα β isoforms. We disclose how morphing heterocyclic core previously discovered 4,6-diaryl quinazolines a significantly less lipophilic...
Sarcoidosis is a disease characterised by granuloma formation. There an unmet need for new treatment strategies beyond corticosteroids. The NLRP3 inflammasome pathway expressed in innate immune cells and senses danger signals to elicit inflammatory interleukin (IL)-1β; it has recently become druggable target. This prompted us test the role of IL-1β formation sarcoidosis.19 sarcoid patients 19 healthy volunteers were recruited into this pilot study. activity was measured bronchoalveolar...
In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. 2020, rare cases retinal vasculitis and/or occlusion (RV/RO) were reported, often during first few months after initiation, consistent with possible immunologic pathobiology. This finding was inconsistent preclinical studies in cynomolgus monkeys that demonstrated no drug-related...
Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although formation ADAs may a prerequisite, other factors likely contribute some having RV/RO, whereas vast majority do not. To identify...
Previous studies have indicated a role for extracellular ATP in the regulation of epidermal homeostasis. Here we investigated expression P2Y 2 receptors by human keratinocytes, cells which comprise epidermis. Reverse transcriptase‐polymerase chain reaction (RT–PCR) revealed mRNA G‐protein‐coupled, receptor primary cultured keratinocytes. In situ hybridization skin sections that transcripts were expressed native tissue. These demonstrated striking pattern localization to basal layer...
A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well hERG channel prevented it further development. Therefore, new round of optimization addressing the key liabilities performed led discovery with an improved profile. Compound significant rat antigen induced arthritis hyperalgesia angiogenesis model at well-tolerated dose 30 mg/kg.
In dystrophic mice, a model of merosin‐deficient congenital muscular dystrophy, laminin‐2 mutations produce peripheral nerve dysmyelination and render Schwann cells unable to sort bundles axons. The laminin receptor the mechanism through which impaired sorting occur are unknown. We describe mice in cell‐specific disruption beta1 integrin, component receptors, causes severe neuropathy with radial Beta1‐null populate nerves, proliferate, survive normally, but do not extend or maintain normal...
Genetic disruption or short-term pharmacological inhibition of MALT1 protease is effective in several preclinical models autoimmunity and B cell malignancies. Despite these protective effects, the severe reduction regulatory T cells (Tregs) associated IPEX-like pathology occurring upon congenital mice has raised concerns about long-term safety inhibition. Here we describe results a series toxicology studies rat dog species using MLT-943, novel potent selective inhibitor. While MLT-943...
Abstract Objective We have previously reported that the kinase activity of interleukin‐1 receptor–associated 4 (IRAK‐4) is important for Toll‐like receptor and signaling in vitro. Using mice devoid IRAK‐4 (IRAK‐4 KD mice), we undertook this study to determine importance function complex disease models joint inflammation. Methods were subjected serum transfer–induced (K/BxN) arthritis, migration transferred spleen lymphocytes into joints cartilage bone degradation assessed. T cell response...
This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical cellular assays, compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis chamber model rodent tumor models at daily doses less than 3...
Background Succinate, in addition to its role as an intermediary of the citric acid cycle, acts alarmin, initiating and propagating danger signals resulting from tissue injury or inflammatory stimuli. The contribution this immune sensing pathway development allergic responses is unknown. Methods Ear thickness wild-type (wt) Sucnr1-deficient (Sucnr1−/−) mice, sensitized challenged with oxazolone, was used a criterion assess relevance SUCNR1/GPR91 expression mediating contact dermatitis (ACD)....
The cytosolic metalloenzyme leukotriene A
Abstract Halting tumor growth by interfering with tumor-induced angiogenesis is an attractive therapeutic approach. Such treatments include humanized antibodies blocking the activity of vascular endothelial factor (VEGF)-A (bevacizumab), soluble VEGF receptor (VEGFR) constructs (VEGF-Trap), or small-molecule inhibitors VEGFR signaling, including PTK787/ZK222584 (PTK/ZK), sorafenib, and sunitinib. PTK/ZK has been shown previously to specifically block VEGF-induced phosphorylation VEGFR-1, -2...