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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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. |
doi_str_mv | 10.3390/ijms20225780 |
format | Article |
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(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.</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 & 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</subject><ispartof>International journal of molecular sciences, 2019-11, Vol.20 (22), p.5780</ispartof><rights>2019. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 by the authors. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-17e29fd66357771a4dd7ed5f2cf94943d96a97c5ee13d9a1bf9bf69013cb47d43</citedby><cites>FETCH-LOGICAL-c412t-17e29fd66357771a4dd7ed5f2cf94943d96a97c5ee13d9a1bf9bf69013cb47d43</cites><orcidid>0000-0002-1790-698X ; 0000-0001-5391-5843 ; 0000-0002-3607-2888</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887705/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887705/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31744223$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Karaś, Kaja</creatorcontrib><creatorcontrib>Sałkowska, Anna</creatorcontrib><creatorcontrib>Karwaciak, Iwona</creatorcontrib><creatorcontrib>Walczak-Drzewiecka, Aurelia</creatorcontrib><creatorcontrib>Dastych, Jarosław</creatorcontrib><creatorcontrib>Bachorz, Rafał A</creatorcontrib><creatorcontrib>Ratajewski, Marcin</creatorcontrib><title>The Dichotomous Nature of AZ5104 (an EGFR Inhibitor) Towards RORγ and RORγT</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><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.</description><subject>Acrylamides - pharmacology</subject><subject>Amino acid sequence</subject><subject>Amino acids</subject><subject>Aniline Compounds - pharmacology</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Autoimmune diseases</subject><subject>Cell differentiation</subject><subject>Cell Survival - drug effects</subject><subject>Chemical compounds</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Epidermal growth factor</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB Receptors - antagonists & inhibitors</subject><subject>ErbB Receptors - metabolism</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Helper cells</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Hydrogen bonds</subject><subject>Indoles - pharmacology</subject><subject>Inflammation - prevention & control</subject><subject>Interferon</subject><subject>Interferon regulatory factor</subject><subject>Interferon regulatory factor 4</subject><subject>Isoforms</subject><subject>Kinases</subject><subject>Leucine zipper proteins</subject><subject>Ligands</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Metabolism</subject><subject>Models, Molecular</subject><subject>Molecular Docking Simulation</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors</subject><subject>Pathogenesis</subject><subject>Pharmacology</subject><subject>Phosphorylation</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Protein Isoforms</subject><subject>Proteins</subject><subject>Proto-Oncogene Mas</subject><subject>Pyrimidines - pharmacology</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Small Molecule Libraries</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - antagonists & inhibitors</subject><subject>Th17 Cells - drug effects</subject><subject>Therapeutic applications</subject><subject>Transcription factors</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1KAzEUhYMoVqs71xJwU8Fq_mbSbIRS21qoFkrduAmZScZO6UxqMqP4XL6Hz2SktVRX98D9ONx7DgBnGF1TKtBNvig8QYREvIP2wBFmhLQRivn-jm6AY-8XCBFKInEIGhRzFnb0CDzM5gbe5encVrawtYePqqqdgTaD3ecIIwZbqoT94WAKR-U8T_LKuks4s-_KaQ-nk-nXJ1SlXqvZCTjI1NKb081sgqdBf9a7b48nw1GvO26nDJOqjbkhItNxTCPOOVZMa250lJE0E0wwqkWsBE8jY3DQCieZSLJYIEzThHHNaBPcrn1XdVIYnZqycmopVy4vlPuQVuXy76bM5_LFvsm40-EcRcGgtTFw9rU2vpJF7lOzXKrShBQkoThmpMMFDejFP3Rha1eG9wJFQ6ARQSJQV2sqddZ7Z7LtMRjJn57kbk8BP999YAv_FkO_Ad64jTw</recordid><startdate>20191117</startdate><enddate>20191117</enddate><creator>Karaś, Kaja</creator><creator>Sałkowska, Anna</creator><creator>Karwaciak, Iwona</creator><creator>Walczak-Drzewiecka, Aurelia</creator><creator>Dastych, Jarosław</creator><creator>Bachorz, Rafał A</creator><creator>Ratajewski, Marcin</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1790-698X</orcidid><orcidid>https://orcid.org/0000-0001-5391-5843</orcidid><orcidid>https://orcid.org/0000-0002-3607-2888</orcidid></search><sort><creationdate>20191117</creationdate><title>The Dichotomous Nature of AZ5104 (an EGFR Inhibitor) Towards RORγ and RORγT</title><author>Karaś, Kaja ; Sałkowska, Anna ; Karwaciak, Iwona ; Walczak-Drzewiecka, Aurelia ; Dastych, Jarosław ; Bachorz, Rafał A ; Ratajewski, Marcin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-17e29fd66357771a4dd7ed5f2cf94943d96a97c5ee13d9a1bf9bf69013cb47d43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acrylamides - pharmacology</topic><topic>Amino acid sequence</topic><topic>Amino acids</topic><topic>Aniline Compounds - pharmacology</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Autoimmune diseases</topic><topic>Cell differentiation</topic><topic>Cell Survival - drug effects</topic><topic>Chemical compounds</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>ErbB Receptors - antagonists & inhibitors</topic><topic>ErbB Receptors - metabolism</topic><topic>Gene expression</topic><topic>Growth factors</topic><topic>Helper cells</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Hydrogen bonds</topic><topic>Indoles - pharmacology</topic><topic>Inflammation - prevention & control</topic><topic>Interferon</topic><topic>Interferon regulatory factor</topic><topic>Interferon regulatory factor 4</topic><topic>Isoforms</topic><topic>Kinases</topic><topic>Leucine zipper proteins</topic><topic>Ligands</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Metabolism</topic><topic>Models, Molecular</topic><topic>Molecular Docking Simulation</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 3 - agonists</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 3 - antagonists & inhibitors</topic><topic>Pathogenesis</topic><topic>Pharmacology</topic><topic>Phosphorylation</topic><topic>Promoter Regions, Genetic - genetics</topic><topic>Protein Isoforms</topic><topic>Proteins</topic><topic>Proto-Oncogene Mas</topic><topic>Pyrimidines - pharmacology</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Small Molecule Libraries</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - antagonists & inhibitors</topic><topic>Th17 Cells - drug effects</topic><topic>Therapeutic applications</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Karaś, Kaja</creatorcontrib><creatorcontrib>Sałkowska, Anna</creatorcontrib><creatorcontrib>Karwaciak, Iwona</creatorcontrib><creatorcontrib>Walczak-Drzewiecka, Aurelia</creatorcontrib><creatorcontrib>Dastych, Jarosław</creatorcontrib><creatorcontrib>Bachorz, Rafał A</creatorcontrib><creatorcontrib>Ratajewski, Marcin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Karaś, Kaja</au><au>Sałkowska, Anna</au><au>Karwaciak, Iwona</au><au>Walczak-Drzewiecka, Aurelia</au><au>Dastych, Jarosław</au><au>Bachorz, Rafał A</au><au>Ratajewski, Marcin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Dichotomous Nature of AZ5104 (an EGFR Inhibitor) Towards RORγ and RORγT</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2019-11-17</date><risdate>2019</risdate><volume>20</volume><issue>22</issue><spage>5780</spage><pages>5780-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>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.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>31744223</pmid><doi>10.3390/ijms20225780</doi><orcidid>https://orcid.org/0000-0002-1790-698X</orcidid><orcidid>https://orcid.org/0000-0001-5391-5843</orcidid><orcidid>https://orcid.org/0000-0002-3607-2888</orcidid><oa>free_for_read</oa></addata></record> |
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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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