Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14
[Display omitted] A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified a...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-07, Vol.27 (13), p.2907-2911 |
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| container_issue | 13 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 27 |
| creator | Upton, Kristen Meyers, Matthew Thorsell, Ann-Gerd Karlberg, Tobias Holechek, Jacob Lease, Robert Schey, Garrett Wolf, Emily Lucente, Adrianna Schüler, Herwig Ferraris, Dana |
| description | [Display omitted]
A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50=160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase. |
| doi_str_mv | 10.1016/j.bmcl.2017.04.089 |
| format | Article |
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A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50=160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.04.089</identifier><identifier>PMID: 28495083</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ARTD-8 ; Dose-Response Relationship, Drug ; Drug Design ; Humans ; Models, Molecular ; Molecular Structure ; Mono(ADP-ribosyl) transferase ; PARP ; PARP14 ; Poly(ADP-ribose) Polymerase Inhibitors - chemistry ; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology ; Poly(ADP-ribose) Polymerases - metabolism ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-07, Vol.27 (13), p.2907-2911</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c394t-96f2f057af89c38a93a620c135b043309b8ccee00a0216c7a9482ab78e7738233</citedby><cites>FETCH-LOGICAL-c394t-96f2f057af89c38a93a620c135b043309b8ccee00a0216c7a9482ab78e7738233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X17304730$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28495083$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:135969171$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Upton, Kristen</creatorcontrib><creatorcontrib>Meyers, Matthew</creatorcontrib><creatorcontrib>Thorsell, Ann-Gerd</creatorcontrib><creatorcontrib>Karlberg, Tobias</creatorcontrib><creatorcontrib>Holechek, Jacob</creatorcontrib><creatorcontrib>Lease, Robert</creatorcontrib><creatorcontrib>Schey, Garrett</creatorcontrib><creatorcontrib>Wolf, Emily</creatorcontrib><creatorcontrib>Lucente, Adrianna</creatorcontrib><creatorcontrib>Schüler, Herwig</creatorcontrib><creatorcontrib>Ferraris, Dana</creatorcontrib><title>Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50=160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase.</description><subject>ARTD-8</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Mono(ADP-ribosyl) transferase</subject><subject>PARP</subject><subject>PARP14</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - chemistry</subject><subject>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</subject><subject>Poly(ADP-ribose) Polymerases - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1vEzEQhi1ERUPoH-CA9lik7jL-2F1b4hK1hSJVIkJU6s3yOrPUYddO7Q1V_n0dEnrkNJ7x876Hh5D3FCoKtPm0rrrRDhUD2lYgKpDqFZlR0YiSC6hfkxmoBkqpxP0peZvSGoAKEOINOWVSqBokn5G7K0zuly-MXxVp56eHvKYi9MUmTOinwvkH17kpxL_H_F2MwYfzxdWyjK4LaTd8nKLxqcdoEl4Uy8WPJRXvyElvhoRnxzknd1-uf17elLffv367XNyWlisxlarpWQ91a3qpLJdGcdMwsJTXHQjOQXXSWkQAA4w2tjVKSGa6VmLbcsk4n5Py0JuecLPt9Ca60cSdDsbp4-l3fqEWqpE5MyfnB34Tw-MW06RHlywOg_EYtklTqRSlDFidUXZAbQwpRexfyinovX691nv9eq9fg9BZfw59OPZvuxFXL5F_vjPw-QBgtvLHYdTJOvQWVy6infQquP_1PwOSrpWC</recordid><startdate>20170701</startdate><enddate>20170701</enddate><creator>Upton, Kristen</creator><creator>Meyers, Matthew</creator><creator>Thorsell, Ann-Gerd</creator><creator>Karlberg, Tobias</creator><creator>Holechek, Jacob</creator><creator>Lease, Robert</creator><creator>Schey, Garrett</creator><creator>Wolf, Emily</creator><creator>Lucente, Adrianna</creator><creator>Schüler, Herwig</creator><creator>Ferraris, Dana</creator><general>Elsevier Ltd</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>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20170701</creationdate><title>Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14</title><author>Upton, Kristen ; Meyers, Matthew ; Thorsell, Ann-Gerd ; Karlberg, Tobias ; Holechek, Jacob ; Lease, Robert ; Schey, Garrett ; Wolf, Emily ; Lucente, Adrianna ; Schüler, Herwig ; Ferraris, Dana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c394t-96f2f057af89c38a93a620c135b043309b8ccee00a0216c7a9482ab78e7738233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>ARTD-8</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Mono(ADP-ribosyl) transferase</topic><topic>PARP</topic><topic>PARP14</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - chemistry</topic><topic>Poly(ADP-ribose) Polymerase Inhibitors - pharmacology</topic><topic>Poly(ADP-ribose) Polymerases - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Upton, Kristen</creatorcontrib><creatorcontrib>Meyers, Matthew</creatorcontrib><creatorcontrib>Thorsell, Ann-Gerd</creatorcontrib><creatorcontrib>Karlberg, Tobias</creatorcontrib><creatorcontrib>Holechek, Jacob</creatorcontrib><creatorcontrib>Lease, Robert</creatorcontrib><creatorcontrib>Schey, Garrett</creatorcontrib><creatorcontrib>Wolf, Emily</creatorcontrib><creatorcontrib>Lucente, Adrianna</creatorcontrib><creatorcontrib>Schüler, Herwig</creatorcontrib><creatorcontrib>Ferraris, Dana</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>SwePub</collection><collection>SwePub Articles</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Upton, Kristen</au><au>Meyers, Matthew</au><au>Thorsell, Ann-Gerd</au><au>Karlberg, Tobias</au><au>Holechek, Jacob</au><au>Lease, Robert</au><au>Schey, Garrett</au><au>Wolf, Emily</au><au>Lucente, Adrianna</au><au>Schüler, Herwig</au><au>Ferraris, Dana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-07-01</date><risdate>2017</risdate><volume>27</volume><issue>13</issue><spage>2907</spage><epage>2911</epage><pages>2907-2911</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50=160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28495083</pmid><doi>10.1016/j.bmcl.2017.04.089</doi><tpages>5</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | ARTD-8 Dose-Response Relationship, Drug Drug Design Humans Models, Molecular Molecular Structure Mono(ADP-ribosyl) transferase PARP PARP14 Poly(ADP-ribose) Polymerase Inhibitors - chemistry Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerases - metabolism Structure-Activity Relationship |
| title | Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14 |
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