Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors
Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibiti...
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| Veröffentlicht in: | PloS one 2014-02, Vol.9 (2), p.e88908 |
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| creator | Muise, Eric S Zhu, Yonghua Verras, Andreas Karanam, Bindhu V Gorski, Judith Weingarth, Drew Lin, Hua V Hwa, Joyce Thompson, John R Hu, Guanghui Liu, Jian He, Shuwen DeVita, Robert J Shen, Dong-Ming Pinto, Shirly |
| description | Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting. |
| doi_str_mv | 10.1371/journal.pone.0088908 |
| format | Article |
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DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0088908</identifier><identifier>PMID: 24558447</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Atrophy ; Atrophy - chemically induced ; Atrophy - enzymology ; Biology ; Biomarkers ; Biomarkers - metabolism ; Biosynthesis ; Chemistry ; Diabetes ; Diacylglycerol ; Diacylglycerol O-acyltransferase ; Diacylglycerol O-Acyltransferase - antagonists & inhibitors ; Diglycerides ; Drug Discovery ; Enzyme Inhibitors - adverse effects ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Hydrophobic and Hydrophilic Interactions ; Inhibition ; Inhibitors ; Laboratories ; Lipids ; Male ; Medicine ; Metabolic disorders ; Metabolic pathways ; Metabolism ; Mice ; Obesity ; Peptides ; Pharmaceutical industry ; Pharmacology ; Physical properties ; R&D ; Research & development ; Ribonucleic acid ; RNA ; Rodents ; Sebaceous gland ; Sebaceous Glands - drug effects ; Sebaceous Glands - pathology ; Skin ; Skin - drug effects ; Skin - enzymology ; Skin - metabolism ; Small Molecule Libraries - adverse effects ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - metabolism ; Small Molecule Libraries - pharmacology ; Tissues ; Vaccines</subject><ispartof>PloS one, 2014-02, Vol.9 (2), p.e88908</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Muise et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Muise et al 2014 Muise et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-8e2c0e79cbbe0e4bc84c7dd155905503b386ba9a9cb54a435fd9b327716e67a53</citedby><cites>FETCH-LOGICAL-c758t-8e2c0e79cbbe0e4bc84c7dd155905503b386ba9a9cb54a435fd9b327716e67a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928314/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928314/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24558447$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Slominski, Andrzej T.</contributor><creatorcontrib>Muise, Eric S</creatorcontrib><creatorcontrib>Zhu, Yonghua</creatorcontrib><creatorcontrib>Verras, Andreas</creatorcontrib><creatorcontrib>Karanam, Bindhu V</creatorcontrib><creatorcontrib>Gorski, Judith</creatorcontrib><creatorcontrib>Weingarth, Drew</creatorcontrib><creatorcontrib>Lin, Hua V</creatorcontrib><creatorcontrib>Hwa, Joyce</creatorcontrib><creatorcontrib>Thompson, John R</creatorcontrib><creatorcontrib>Hu, Guanghui</creatorcontrib><creatorcontrib>Liu, Jian</creatorcontrib><creatorcontrib>He, Shuwen</creatorcontrib><creatorcontrib>DeVita, Robert J</creatorcontrib><creatorcontrib>Shen, Dong-Ming</creatorcontrib><creatorcontrib>Pinto, Shirly</creatorcontrib><title>Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Inhibition of Diacylglycerol O-acyltransferase 1 (DGAT1) has been a mechanism of interest for metabolic disorders. DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.</description><subject>Animals</subject><subject>Atrophy</subject><subject>Atrophy - chemically induced</subject><subject>Atrophy - enzymology</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Biomarkers - metabolism</subject><subject>Biosynthesis</subject><subject>Chemistry</subject><subject>Diabetes</subject><subject>Diacylglycerol</subject><subject>Diacylglycerol O-acyltransferase</subject><subject>Diacylglycerol O-Acyltransferase - antagonists & inhibitors</subject><subject>Diglycerides</subject><subject>Drug Discovery</subject><subject>Enzyme Inhibitors - adverse effects</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Hydrophobic and Hydrophilic Interactions</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Laboratories</subject><subject>Lipids</subject><subject>Male</subject><subject>Medicine</subject><subject>Metabolic disorders</subject><subject>Metabolic pathways</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Obesity</subject><subject>Peptides</subject><subject>Pharmaceutical industry</subject><subject>Pharmacology</subject><subject>Physical properties</subject><subject>R&D</subject><subject>Research & development</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Rodents</subject><subject>Sebaceous gland</subject><subject>Sebaceous Glands - drug effects</subject><subject>Sebaceous Glands - pathology</subject><subject>Skin</subject><subject>Skin - drug effects</subject><subject>Skin - enzymology</subject><subject>Skin - metabolism</subject><subject>Small Molecule Libraries - adverse effects</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - metabolism</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Tissues</subject><subject>Vaccines</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl-L1DAUxYso7rr6DUQLguDDjPnbJC_CsOo6sLCgqz6GJE3bDJ1mNknF9dObcbrLFBQkDwk3v3tyOTlF8RyCJcQMvt34MQyqX-78YJcAcC4Af1CcQoHRokIAPzw6nxRPYtwAQDGvqsfFCSKUckLYafF9XdshucYZlZwfSjXUpelUUCbZ4H4dir4po9XKWD_Gsu33jErB77rbRdyp4Ia2fH-xuoalGzqnXfIhPi0eNaqP9tm0nxVfP364Pv-0uLy6WJ-vLheGUZ4W3CIDLBNGawss0YYTw-oaUioApQDrPLBWQmWAEkUwbWqhMWIMVrZiiuKz4uVBd9f7KCdPooRECI4qikQm1gei9mojd8FtVbiVXjn5p-BDK1VIzvRWYmCF5bpmEFBSs0pThJAgtmlgbRHev_Zuem3UW1ubbF1Q_Ux0fjO4Trb-h8QCcQxJFng1CQR_M9qY_jHyRLUqT-WGxmcxs3XRyBVhnAOUfzJTy79QedV260xOReNyfdbwZtaQmWR_plaNMcr1l8__z159m7Ovj9jOqj510ffjPjtxDpIDaIKPMdjm3jkI5D7Ud27IfajlFOrc9uLY9fumuxTj34LD8kI</recordid><startdate>20140218</startdate><enddate>20140218</enddate><creator>Muise, Eric S</creator><creator>Zhu, Yonghua</creator><creator>Verras, Andreas</creator><creator>Karanam, Bindhu V</creator><creator>Gorski, Judith</creator><creator>Weingarth, Drew</creator><creator>Lin, Hua V</creator><creator>Hwa, Joyce</creator><creator>Thompson, John R</creator><creator>Hu, Guanghui</creator><creator>Liu, Jian</creator><creator>He, Shuwen</creator><creator>DeVita, Robert J</creator><creator>Shen, Dong-Ming</creator><creator>Pinto, Shirly</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20140218</creationdate><title>Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors</title><author>Muise, Eric S ; Zhu, Yonghua ; Verras, Andreas ; Karanam, Bindhu V ; Gorski, Judith ; Weingarth, Drew ; Lin, Hua V ; Hwa, Joyce ; Thompson, John R ; Hu, Guanghui ; Liu, Jian ; He, Shuwen ; DeVita, Robert J ; Shen, Dong-Ming ; Pinto, Shirly</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-8e2c0e79cbbe0e4bc84c7dd155905503b386ba9a9cb54a435fd9b327716e67a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Atrophy</topic><topic>Atrophy - chemically induced</topic><topic>Atrophy - enzymology</topic><topic>Biology</topic><topic>Biomarkers</topic><topic>Biomarkers - metabolism</topic><topic>Biosynthesis</topic><topic>Chemistry</topic><topic>Diabetes</topic><topic>Diacylglycerol</topic><topic>Diacylglycerol O-acyltransferase</topic><topic>Diacylglycerol O-Acyltransferase - antagonists & inhibitors</topic><topic>Diglycerides</topic><topic>Drug Discovery</topic><topic>Enzyme Inhibitors - adverse effects</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Hydrophobic and Hydrophilic Interactions</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Laboratories</topic><topic>Lipids</topic><topic>Male</topic><topic>Medicine</topic><topic>Metabolic disorders</topic><topic>Metabolic pathways</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Obesity</topic><topic>Peptides</topic><topic>Pharmaceutical industry</topic><topic>Pharmacology</topic><topic>Physical properties</topic><topic>R&D</topic><topic>Research & development</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Rodents</topic><topic>Sebaceous gland</topic><topic>Sebaceous Glands - 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DGAT1 inhibition has been shown to be a key regulator in an array of metabolic pathways; however, based on the DGAT1 KO mouse phenotype the anticipation is that pharmacological inhibition of DGAT1 could potentially lead to skin related adverse effects. One of the aims in developing small molecule DGAT1 inhibitors that target key metabolic tissues is to avoid activity on skin-localized DGAT1 enzyme. In this report we describe a modeling-based approach to identify molecules with physical properties leading to differential exposure distribution. In addition, we demonstrate histological and RNA based biomarker approaches that can detect sebaceous gland atrophy pre-clinically that could be used as potential biomarkers in a clinical setting.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24558447</pmid><doi>10.1371/journal.pone.0088908</doi><tpages>e88908</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-02, Vol.9 (2), p.e88908 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1499826529 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Atrophy Atrophy - chemically induced Atrophy - enzymology Biology Biomarkers Biomarkers - metabolism Biosynthesis Chemistry Diabetes Diacylglycerol Diacylglycerol O-acyltransferase Diacylglycerol O-Acyltransferase - antagonists & inhibitors Diglycerides Drug Discovery Enzyme Inhibitors - adverse effects Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Hydrophobic and Hydrophilic Interactions Inhibition Inhibitors Laboratories Lipids Male Medicine Metabolic disorders Metabolic pathways Metabolism Mice Obesity Peptides Pharmaceutical industry Pharmacology Physical properties R&D Research & development Ribonucleic acid RNA Rodents Sebaceous gland Sebaceous Glands - drug effects Sebaceous Glands - pathology Skin Skin - drug effects Skin - enzymology Skin - metabolism Small Molecule Libraries - adverse effects Small Molecule Libraries - chemistry Small Molecule Libraries - metabolism Small Molecule Libraries - pharmacology Tissues Vaccines |
| title | Identification and characterization of sebaceous gland atrophy-sparing DGAT1 inhibitors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-02T02%3A16%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20and%20characterization%20of%20sebaceous%20gland%20atrophy-sparing%20DGAT1%20inhibitors&rft.jtitle=PloS%20one&rft.au=Muise,%20Eric%20S&rft.date=2014-02-18&rft.volume=9&rft.issue=2&rft.spage=e88908&rft.pages=e88908-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0088908&rft_dat=%3Cgale_plos_%3EA478802053%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1499826529&rft_id=info:pmid/24558447&rft_galeid=A478802053&rft_doaj_id=oai_doaj_org_article_30e9e8bd71054d76b522294eff1de235&rfr_iscdi=true |