A5087465587- Cytokine Signaling Pathways and Interactions
- Melanoma and MAPK Pathways
- Protein Kinase Regulation and GTPase Signaling
- Rheumatoid Arthritis Research and Therapies
- NF-κB Signaling Pathways
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Pharmacological Effects of Natural Compounds
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Autoimmune and Inflammatory Disorders Research
- Immune Cell Function and Interaction
- Chronic Myeloid Leukemia Treatments
- Systemic Lupus Erythematosus Research
- Synthesis and biological activity
- Cellular Mechanics and Interactions
- Click Chemistry and Applications
- Psoriasis: Treatment and Pathogenesis
- Receptor Mechanisms and Signaling
- 14-3-3 protein interactions
- interferon and immune responses
- Cancer Mechanisms and Therapy
- Microbial Natural Products and Biosynthesis
- Computational Drug Discovery Methods
- Marine Sponges and Natural Products
- PI3K/AKT/mTOR signaling in cancer
Pfizer (United States)
2011-2023
Inflammation Research Foundation
2005-2009
University of British Columbia
2004
University of Amsterdam
2004
Tufts University
1996-2001
Institut pour la Recherche sur le Cancer de Lille
1991-1995
Inserm
1995
<h2>Summary</h2> Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For global view IFN signatures regulatory pathways, we performed gene expression chromatin analyses the IFN-induced response across range immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, sensitivity tonic revealed underlying changes in configuration. We combined...
Mitogen-activated protein kinase (MAPK)-activated 2 (MK2) is activated upon stress by p38 MAPKα and -β, which bind to a basic docking motif in the C terminus of MK2 subsequently phosphorylate its regulatory sites. As result activation exported from nucleus cytoplasm cotransports active MAPK this compartment. Here we show that amount significantly reduced cells tissues lacking MK2, indicating stabilizing effect for p38. Using murine knockout model, have previously shown elimination leads...
MK2 and MK3 represent protein kinases downstream of p38 mitogen-activated kinase (MAPK).Deletion the gene in mice resulted an impaired inflammatory response although MK3, which displays extensive structural similarities identical functional properties vitro, is still present.Here, we analyze tumor necrosis factor (TNF) production expression MAPK tristetraprolin (TTP) MK3-deficient demonstrate that there are no significant differences with wild-type animals.We show vivo expressed activated...
PF-06651600, a newly discovered potent JAK3-selective inhibitor, is highly efficacious at inhibiting γc cytokine signaling, which dependent on both JAK1 and JAK3. PF-06651600 allowed the comparison of inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells level that could not be achieved previously without such potency selectivity. In vitro, inhibits Th1 Th17 cell differentiation function, vivo it reduces disease pathology rat adjuvant-induced arthritis as well mouse...
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator transcription (STAT) pathway. JAK1 for γ-common chain cytokines, interleukin (IL)-6, type-I interferon (IFN) family, while TYK2 in addition to IFN also plays a role IL-23 IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or inhibitors has demonstrated efficacy Phase III psoriasis, psoriatic arthritis,...
Janus kinases (JAKs) are intracellular tyrosine that mediate the signaling of numerous cytokines and growth factors involved in regulation immunity, inflammation, hematopoiesis. As JAK1 pairs with JAK2, JAK3, TYK2, a JAK1-selective inhibitor would be expected to inhibit many inflammation immune function while avoiding inhibition JAK2 homodimer regulating erythropoietin thrombopoietin signaling. Our efforts began tofacitinib, an oral JAK approved for treatment rheumatoid arthritis. Through...
Significant work has been dedicated to the discovery of JAK kinase inhibitors resulting in several compounds entering clinical development and two FDA approved NMEs. However, despite significant effort during past 2 decades, identification highly selective JAK3 eluded scientific community. A within our research organization resulted first orally active specific inhibitor, which achieves isoform specificity through covalent interaction with a unique residue Cys-909. The relatively rapid...
PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level toward is achieved by covalent interaction a unique cysteine residue (Cys-909) in catalytic domain JAK3, which replaced serine Importantly, 10 kinases kinome have at equivalent position Cys-909 JAK3. Five those belong to TEC kinase family including BTK, BMX, ITK, RLK, and are also inhibited PF-06651600. Preclinical data demonstrate that inhibition cytolytic function...
Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such rheumatoid arthritis (RA). JAK function intracellularly by modulating the catalytic activity JAKs and disrupting receptor-mediated signaling multiple cytokines growth factors, including those with pro-inflammatory activity. Understanding inhibition profiles different inhibitors, based on associated cytokine receptors downstream pathways affected, is important to identify...
Abstract TNF-α is a pleiotropic cytokine considered primary mediator of immune regulation and inflammatory response has been shown to play central role in rheumatoid arthritis (RA). MAPKAP kinase 2 (MK2) serine/threonine that regulated through direct phosphorylation by p38 MAPK, be an essential component the regulates biosynthesis at posttranscriptional level. The murine model collagen-induced (CIA) established disease study pathogenic mechanisms relevant RA. In this study, we report...
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent that engage residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated inhibitors. Through crystallography, kinetic, computational studies, interaction cyanamide 12 with was optimized leading potent as exemplified 32. In relevant cell-based assays agreement previous results this group, 32 demonstrated...
We have recently shown that the neuronal exchange factor p140 Ras-GRF becomes activated in vivo response to elevated calcium levels [C. L. Farnsworth, N. W. Freshney, B. Rosen, A. Ghosh, M. E. Greenberg, and Feig, Nature (London) 376:524-527, 1995]. Activation is mediated by calcium-induced calmodulin binding an IQ domain near N terminus of Ras-GRF. Here we show adjacent N-terminal pleckstrin homology (PH), coiled-coil, domains function cooperatively allow activation. Deletion PH...
Significance JAK kinase inhibitors (JAKis) have advanced options for treatment of autoimmune diseases. Because JAKs are signaling hubs several cytokine receptors, JAKis’ overall impact on the immune system and how they actually improve diseases like rheumatoid arthritis remain poorly understood. Combined immunophenotyping genomic profiling revealed broad JAKi effects immunogenomic network, irrespective inhibitor fine specificity, with population homeostasis coregulated gene-expression...
Kinases constitute an important class of therapeutic targets being explored both by academia and the pharmaceutical industry. The major focus this effort was directed toward identification ATP competitive inhibitors. Although it has long been recognized that intracellular concentration is very different from concentrations utilized in biochemical enzyme assays, little thought devoted to incorporating discrepancy into our understanding translation inhibition cellular function. Significant...
Engagement of the tumor necrosis factor-α (TNF-α) receptors by TNF-α ligand results in rapid induction gene expression. The study presented here shows that autoregulation transcription selective signaling through factor receptor 1 (TNFR1) requires p38 mitogen-activated protein (MAP) kinase activity and binding factors ATF-2 Jun to cAMP-response element (CRE) promoter element. Consistent with these findings, TNFR1 engagement increased MAP p38-dependent phosphorylation ATF-2. Furthermore,...
Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine that controls the initiation and progression of inflammatory diseases such as rheumatoid arthritis. Tpl2 MAPKKK in MAPK (i.e. ERK) pathway, Tpl2-MEK-ERK signaling pathway activated by mediators TNFα, interleukin (IL)-1β, bacterial endotoxin (lipopolysaccharide (LPS)). Moreover, required for TNFα expression. Thus, pharmacologic inhibition should be valid approach to therapeutic intervention pathogenesis arthritis other humans. We...
Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined disposition abrocitinib in male participants following and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters characterize metabolite (M) profiles. The results indicated had a systemic clearance 64.2 L/h, steady-state volume distribution 100 L, extent absorption...