Structure–Activity Relationship Studies of α‑Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family
The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various p...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-09, Vol.63 (17), p.9340-9359 |
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| creator | Zhou, Juan Mock, Elliot D Al Ayed, Karol Di, Xinyu Kantae, Vasudev Burggraaff, Lindsey Stevens, Anna F Martella, Andrea Mohr, Florian Jiang, Ming van der Wel, Tom Wendel, Tiemen J Ofman, Tim P Tran, Yvonne de Koster, Nicky van Westen, Gerard J.P Hankemeier, Thomas van der Stelt, Mario |
| description | The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs. |
| doi_str_mv | 10.1021/acs.jmedchem.0c00522 |
| format | Article |
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NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c00522</identifier><identifier>PMID: 32787138</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acyltransferases - antagonists & inhibitors ; Acyltransferases - chemistry ; Amides - chemistry ; Amides - pharmacology ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Hep G2 Cells ; Humans ; Models, Molecular ; Phospholipases - antagonists & inhibitors ; Phospholipases - chemistry ; Protein Conformation ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2020-09, Vol.63 (17), p.9340-9359</ispartof><rights>Copyright © 2020 American Chemical Society 2020 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-db860b29f034ba1c5a860ccef7e68043f7bd97c791640ec21ae2bc5d0775de2f3</citedby><cites>FETCH-LOGICAL-a449t-db860b29f034ba1c5a860ccef7e68043f7bd97c791640ec21ae2bc5d0775de2f3</cites><orcidid>0000-0003-0717-1817 ; 0000-0002-2442-0443 ; 0000-0002-1500-2856 ; 0000-0002-1181-7134 ; 0000-0001-7871-2073 ; 0000-0002-1029-5717</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c00522$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00522$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32787138$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Juan</creatorcontrib><creatorcontrib>Mock, Elliot D</creatorcontrib><creatorcontrib>Al Ayed, Karol</creatorcontrib><creatorcontrib>Di, Xinyu</creatorcontrib><creatorcontrib>Kantae, Vasudev</creatorcontrib><creatorcontrib>Burggraaff, Lindsey</creatorcontrib><creatorcontrib>Stevens, Anna F</creatorcontrib><creatorcontrib>Martella, Andrea</creatorcontrib><creatorcontrib>Mohr, Florian</creatorcontrib><creatorcontrib>Jiang, Ming</creatorcontrib><creatorcontrib>van der Wel, Tom</creatorcontrib><creatorcontrib>Wendel, Tiemen J</creatorcontrib><creatorcontrib>Ofman, Tim P</creatorcontrib><creatorcontrib>Tran, Yvonne</creatorcontrib><creatorcontrib>de Koster, Nicky</creatorcontrib><creatorcontrib>van Westen, Gerard J.P</creatorcontrib><creatorcontrib>Hankemeier, Thomas</creatorcontrib><creatorcontrib>van der Stelt, Mario</creatorcontrib><title>Structure–Activity Relationship Studies of α‑Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. 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Mock, Elliot D ; Al Ayed, Karol ; Di, Xinyu ; Kantae, Vasudev ; Burggraaff, Lindsey ; Stevens, Anna F ; Martella, Andrea ; Mohr, Florian ; Jiang, Ming ; van der Wel, Tom ; Wendel, Tiemen J ; Ofman, Tim P ; Tran, Yvonne ; de Koster, Nicky ; van Westen, Gerard J.P ; Hankemeier, Thomas ; van der Stelt, Mario</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-db860b29f034ba1c5a860ccef7e68043f7bd97c791640ec21ae2bc5d0775de2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Acyltransferases - antagonists & inhibitors</topic><topic>Acyltransferases - chemistry</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Phospholipases - antagonists & inhibitors</topic><topic>Phospholipases - chemistry</topic><topic>Protein Conformation</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhou, Juan</creatorcontrib><creatorcontrib>Mock, Elliot D</creatorcontrib><creatorcontrib>Al Ayed, Karol</creatorcontrib><creatorcontrib>Di, Xinyu</creatorcontrib><creatorcontrib>Kantae, Vasudev</creatorcontrib><creatorcontrib>Burggraaff, Lindsey</creatorcontrib><creatorcontrib>Stevens, Anna F</creatorcontrib><creatorcontrib>Martella, Andrea</creatorcontrib><creatorcontrib>Mohr, Florian</creatorcontrib><creatorcontrib>Jiang, Ming</creatorcontrib><creatorcontrib>van der Wel, Tom</creatorcontrib><creatorcontrib>Wendel, Tiemen J</creatorcontrib><creatorcontrib>Ofman, Tim P</creatorcontrib><creatorcontrib>Tran, Yvonne</creatorcontrib><creatorcontrib>de Koster, Nicky</creatorcontrib><creatorcontrib>van Westen, Gerard J.P</creatorcontrib><creatorcontrib>Hankemeier, Thomas</creatorcontrib><creatorcontrib>van der Stelt, Mario</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, Juan</au><au>Mock, Elliot D</au><au>Al Ayed, Karol</au><au>Di, Xinyu</au><au>Kantae, Vasudev</au><au>Burggraaff, Lindsey</au><au>Stevens, Anna F</au><au>Martella, Andrea</au><au>Mohr, Florian</au><au>Jiang, Ming</au><au>van der Wel, Tom</au><au>Wendel, Tiemen J</au><au>Ofman, Tim P</au><au>Tran, Yvonne</au><au>de Koster, Nicky</au><au>van Westen, Gerard J.P</au><au>Hankemeier, Thomas</au><au>van der Stelt, Mario</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–Activity Relationship Studies of α‑Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-09-10</date><risdate>2020</risdate><volume>63</volume><issue>17</issue><spage>9340</spage><epage>9359</epage><pages>9340-9359</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure–activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32787138</pmid><doi>10.1021/acs.jmedchem.0c00522</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-0717-1817</orcidid><orcidid>https://orcid.org/0000-0002-2442-0443</orcidid><orcidid>https://orcid.org/0000-0002-1500-2856</orcidid><orcidid>https://orcid.org/0000-0002-1181-7134</orcidid><orcidid>https://orcid.org/0000-0001-7871-2073</orcidid><orcidid>https://orcid.org/0000-0002-1029-5717</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2020-09, Vol.63 (17), p.9340-9359 |
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| subjects | Acyltransferases - antagonists & inhibitors Acyltransferases - chemistry Amides - chemistry Amides - pharmacology Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Hep G2 Cells Humans Models, Molecular Phospholipases - antagonists & inhibitors Phospholipases - chemistry Protein Conformation Structure-Activity Relationship |
| title | Structure–Activity Relationship Studies of α‑Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family |
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