The Dichotomous Nature of AZ5104 (an EGFR Inhibitor) Towards RORγ and RORγT

The (RAR related orphan receptor C) gene produces two isoforms by alternative promoter usage: RORγ (nuclear receptor ROR-gamma isoform 1) and RORγT (nuclear receptor ROR-gamma isoform 1). Both proteins have distinct tissue distributions and are involved in several physiological processes, including...

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Veröffentlicht in:International journal of molecular sciences 2019-11, Vol.20 (22), p.5780
Hauptverfasser: Karaś, Kaja, Sałkowska, Anna, Karwaciak, Iwona, Walczak-Drzewiecka, Aurelia, Dastych, Jarosław, Bachorz, Rafał A, Ratajewski, Marcin
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container_issue 22
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container_title International journal of molecular sciences
container_volume 20
creator Karaś, Kaja
Sałkowska, Anna
Karwaciak, Iwona
Walczak-Drzewiecka, Aurelia
Dastych, Jarosław
Bachorz, Rafał A
Ratajewski, Marcin
description The (RAR related orphan receptor C) gene produces two isoforms by alternative promoter usage: RORγ (nuclear receptor ROR-gamma isoform 1) and RORγT (nuclear receptor ROR-gamma isoform 1). Both proteins have distinct tissue distributions and are involved in several physiological processes, including glucose/lipid metabolism and the development of Th17 lymphocytes. Previously, we developed a stably transfected reporter cell line and used it to screen a library of kinase inhibitors. We found that AZ5104 acts as an RORγ agonist at low micromolar concentrations. Molecular docking analysis showed that this compound occupies the ligand binding domain of the receptor with a significant docking score. However, analysis of the biological activity of this compound in Th17 cells revealed that it downregulates RORγT expression and Th17-related cytokine production via inhibition of SRC-ERK-STAT3 (SRC proto-oncogene - extracellular regulated MAP kinase - signal transducer and activator of transcription 3). We thus identified a compound acting as an agonist of RORγ that, due to the inhibition of downstream elements of EGFR (epidermal growth factor receptor) signaling, exerts different biological activity towards a Th17-specific isoform. Additionally, our results may be relevant in the future for the design of treatments targeting signaling pathways that inhibit Th17-related inflammation in certain autoimmune disorders.
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Both proteins have distinct tissue distributions and are involved in several physiological processes, including glucose/lipid metabolism and the development of Th17 lymphocytes. Previously, we developed a stably transfected reporter cell line and used it to screen a library of kinase inhibitors. We found that AZ5104 acts as an RORγ agonist at low micromolar concentrations. Molecular docking analysis showed that this compound occupies the ligand binding domain of the receptor with a significant docking score. However, analysis of the biological activity of this compound in Th17 cells revealed that it downregulates RORγT expression and Th17-related cytokine production via inhibition of SRC-ERK-STAT3 (SRC proto-oncogene - extracellular regulated MAP kinase - signal transducer and activator of transcription 3). We thus identified a compound acting as an agonist of RORγ that, due to the inhibition of downstream elements of EGFR (epidermal growth factor receptor) signaling, exerts different biological activity towards a Th17-specific isoform. Additionally, our results may be relevant in the future for the design of treatments targeting signaling pathways that inhibit Th17-related inflammation in certain autoimmune disorders.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms20225780</identifier><identifier>PMID: 31744223</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Acrylamides - pharmacology ; Amino acid sequence ; Amino acids ; Aniline Compounds - pharmacology ; Animals ; Anti-Inflammatory Agents - pharmacology ; Autoimmune diseases ; Cell differentiation ; Cell Survival - drug effects ; Chemical compounds ; Cytokines ; Cytokines - metabolism ; Epidermal growth factor ; Epidermal growth factor receptors ; ErbB Receptors - antagonists &amp; inhibitors ; ErbB Receptors - metabolism ; Gene expression ; Growth factors ; Helper cells ; Hep G2 Cells ; Humans ; Hydrogen bonds ; Indoles - pharmacology ; Inflammation - prevention &amp; control ; Interferon ; Interferon regulatory factor ; Interferon regulatory factor 4 ; Isoforms ; Kinases ; Leucine zipper proteins ; Ligands ; Lymphocytes ; Lymphocytes T ; Metabolism ; Models, Molecular ; Molecular Docking Simulation ; Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists ; Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists &amp; inhibitors ; Pathogenesis ; Pharmacology ; Phosphorylation ; Promoter Regions, Genetic - genetics ; Protein Isoforms ; Proteins ; Proto-Oncogene Mas ; Pyrimidines - pharmacology ; Signal transduction ; Signal Transduction - drug effects ; Small Molecule Libraries ; Stat3 protein ; STAT3 Transcription Factor - antagonists &amp; inhibitors ; Th17 Cells - drug effects ; Therapeutic applications ; Transcription factors</subject><ispartof>International journal of molecular sciences, 2019-11, Vol.20 (22), p.5780</ispartof><rights>2019. 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source MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central
subjects Acrylamides - pharmacology
Amino acid sequence
Amino acids
Aniline Compounds - pharmacology
Animals
Anti-Inflammatory Agents - pharmacology
Autoimmune diseases
Cell differentiation
Cell Survival - drug effects
Chemical compounds
Cytokines
Cytokines - metabolism
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - metabolism
Gene expression
Growth factors
Helper cells
Hep G2 Cells
Humans
Hydrogen bonds
Indoles - pharmacology
Inflammation - prevention & control
Interferon
Interferon regulatory factor
Interferon regulatory factor 4
Isoforms
Kinases
Leucine zipper proteins
Ligands
Lymphocytes
Lymphocytes T
Metabolism
Models, Molecular
Molecular Docking Simulation
Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists
Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors
Pathogenesis
Pharmacology
Phosphorylation
Promoter Regions, Genetic - genetics
Protein Isoforms
Proteins
Proto-Oncogene Mas
Pyrimidines - pharmacology
Signal transduction
Signal Transduction - drug effects
Small Molecule Libraries
Stat3 protein
STAT3 Transcription Factor - antagonists & inhibitors
Th17 Cells - drug effects
Therapeutic applications
Transcription factors
title The Dichotomous Nature of AZ5104 (an EGFR Inhibitor) Towards RORγ and RORγT
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