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4 results on '"Toll/IL-1R"'

2. Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018).

Author

McElroy WT

Subjects
Animals, Arthritis, Rheumatoid enzymology, Autoimmune Diseases drug therapy, Autoimmune Diseases enzymology, Drug Development methods, Humans, Interleukin-1 Receptor-Associated Kinases metabolism, Neoplasms drug therapy, Neoplasms enzymology, Patents as Topic, Receptors, Interleukin-1 metabolism, Arthritis, Rheumatoid drug therapy, Interleukin-1 Receptor-Associated Kinases antagonists & inhibitors, Protein Kinase Inhibitors pharmacology
Abstract

Introduction: Interleukin-1 receptor-associated kinase 4 (IRAK4) is the most upstream kinase in Toll/Interleukin-1 receptor (TIR) signaling. Human and rodent genetics support the role of IRAK4 in immune function and the involvement of IRAK4-dependent signaling in certain cancers is hypothesized. The accumulating evidence has motivated the discovery of IRAK4 inhibitors that could be used therapeutically., Areas Covered: This review summarizes patents published in 2016-2018 claiming IRAK4 inhibitors. Representative analogues from each patent are presented with a focus on compounds that have been profiled in cellular and in vivo assays., Expert Opinion: The last three years have seen an increased number of IRAK4 inhibitors with which to assess the therapeutic potential of the target. At least 5 companies are believed to have advanced to the clinic. Pfizer is in phase II for rheumatoid arthritis (RA). The outcomes of these studies should inform on the therapeutic potential in autoimmune disease and cancer.

Published
2019
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3. Mapping the Transcriptional Machinery of the IL-8 Gene in Human Bronchial Epithelial Cells

Author

Valentino Bezzerri, Roberto Gambari, Giulio Cabrini, Anna Tamanini, Monica Borgatti, and Alessia Finotti

Subjects
Transcription, Genetic, PRR, pattern recognition receptor, heat shock protein 27, HSP27 Heat-Shock Proteins, Electrophoretic Mobility Shift Assay, HSP27, Ribosomal s6 kinase, cystic fibrosis, ASGM1R, asialo-GM1 receptor, CF, CFTR, cystic fibrosis transmembrane conductance regulator, ChIP, chromatin immunoprecipitation, Ct, threshold cycle, ISA, intermediate sequence A, ISB, intermediate sequence B, MSK, mitogen- and stressactivated kinase, ODN, oligodeoxynucleotide, RSK, 90-kDa ribosomal S6 kinase, TF, transcription factor, TIR, Toll/IL-1R, Transcription (biology), Immunology and Allergy, Reverse Transcriptase Polymerase Chain Reaction, Kinase, Transfection, Mitogen-activated protein kinase, Pseudomonas aeruginosa, Signal Transduction, Immunology, Bronchi, Respiratory Mucosa, Biology, Real-Time Polymerase Chain Reaction, CREB, Ribosomal Protein S6 Kinases, 90-kDa, Humans, Pseudomonas Infections, Interleukin 8, Transcription factor, Interleukin-8, Epithelial Cells, Phosphoproteins, Gene Expression Regulation, biology.protein, Cancer research
Abstract

IL-8 released from bronchial epithelial cells infected with Pseudomonas aeruginosa plays a crucial role in the chronic lung pathology of patients affected by cystic fibrosis. Novel anti-inflammatory approaches will benefit from a thorough understanding of the regulatory mechanisms involved in the transcription of this chemokine to identify potential pharmacological targets. We addressed this issue by investigating the role of phosphoproteins and transcription factors (TFs) on transcription of IL-8 gene in the human bronchial epithelial IB3-1, CuFi-1, and Calu-3 cells. P. aeruginosa increased the basal phosphorylation of the ERK1/2 pathway components 90-kDa ribosomal S6 kinase (RSK)1/2 and mitogen- and stress-activated kinase-2 and of the p38 MAPK pathway components p38α/δ/γ and heat shock protein 27 (HSP27). The involvement of these kinases in the expression of IL-8 gene was confirmed with pharmacological inhibitors of ERK1/2, RSK, p38, and HSP27 both at transcription and secretion levels. Transfection of TF decoy oligodeoxynucleotides, designed to interfere with the interaction of the TFs NF-κB, NF-IL6, AP-1, CREB, and CHOP with the corresponding consensus sequences identified in the IL-8 promoter, reduced the P. aeruginosa-dependent transcription of IL-8, suggesting their participation in the transcriptional machinery. Stimulation of IB3-1 cells with IL-1β led to a similar pattern of activation, whereas the pattern of phosphoproteins and of TFs modulated by TNF-α differentiated sharply. In conclusion, the results highlight a novel role for RSK1/2 and HSP27 phosphoproteins and of the cooperative role of the TFs NF-κB, NF-IL6, AP-1, CHOP, and CREB in P. aeruginosa-dependent induction of transcription of the IL-8 gene in human bronchial epithelial cells.

Published
2011

4. The structural network of inflammation and cancer: merits and challenges.

Author

Guven Maiorov E, Keskin O, Gursoy A, and Nussinov R

Subjects
Inflammation genetics, Models, Molecular, Mutation, Myeloid Differentiation Factor 88 chemistry, Myeloid Differentiation Factor 88 genetics, Myeloid Differentiation Factor 88 metabolism, Neoplasms genetics, Protein Interaction Mapping methods, Protein Interaction Maps, Protein Structure, Tertiary, Toll-Like Receptors chemistry, Toll-Like Receptors genetics, Inflammation metabolism, Neoplasms metabolism, Signal Transduction, Toll-Like Receptors metabolism
Abstract

Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Published
2013
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