Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening
[Display omitted] The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. A...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-02, Vol.27 (4), p.929-935 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 935 |
|---|---|
| container_issue | 4 |
| container_start_page | 929 |
| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 27 |
| creator | Jernigan, Finith E. Hanai, Jun-ichi Sukhatme, Vikas P. Sun, Lijun |
| description | [Display omitted]
The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC50 of the most potent ACL inhibitor A1 is 4.1μM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer. |
| doi_str_mv | 10.1016/j.bmcl.2017.01.001 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1862762829</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0960894X1730001X</els_id><sourcerecordid>1862762829</sourcerecordid><originalsourceid>FETCH-LOGICAL-c356t-e071a887f7f7d9bf801c826eb911204ee4157d112fd1c805ac92ee1562eca3ba3</originalsourceid><addsrcrecordid>eNp9kM1q3DAURkVJaaZpX6CLoGU2dnU1si1DNiH9SSDQLlLoTsjy9ViDx5pIsqnfvjKTZBmE0AWd74N7CPkCLAcG5dd93hzMkHMGVc4gZwzekQ2IUmRbwYozsmF1yTJZi7_n5GMI-wQIJsQHcs4l8LqWbEOWbzYYN6NfqOtoN3k9UqN94_4tg45IW_R21tHOGKgOdEzoQO3Y28ZG58Maunn8nRkb_YoPiw5IZ6vT9XHSA-3trs9i7920649TpMF4xNGOu0_kfaeHgJ-f3wvy58f3x9u77OHXz_vbm4fMbIsyZsgq0FJWXTpt3XSSgZG8xKYG4EwgCiiqNs1dmz5YoU3NEaEoORq9bfT2glydeo_ePU0YojqklXEY9IhuCgpkyauSS14nlJ9Q410IHjt19Pag_aKAqVW52qtVuVqVKwYqGU2hy-f-qTlg-xp5cZyA6xOAacvZolfBWBwNttajiap19q3-_w4glP0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1862762829</pqid></control><display><type>article</type><title>Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Jernigan, Finith E. ; Hanai, Jun-ichi ; Sukhatme, Vikas P. ; Sun, Lijun</creator><creatorcontrib>Jernigan, Finith E. ; Hanai, Jun-ichi ; Sukhatme, Vikas P. ; Sun, Lijun</creatorcontrib><description>[Display omitted]
The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC50 of the most potent ACL inhibitor A1 is 4.1μM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.01.001</identifier><identifier>PMID: 28129980</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ATP Citrate (pro-S)-Lyase - antagonists & inhibitors ; ATP citrate lyase inhibitor ; Cancer metabolism ; Cancer stemness ; Carboxylic Acids - chemistry ; Carboxylic Acids - pharmacology ; Cell Line ; Drug Discovery ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Furans - chemistry ; Furoic acid ; High-Throughput Screening Assays ; Humans ; Molecular Docking Simulation ; Molecular Structure ; Virtual screening</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-02, Vol.27 (4), p.929-935</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-c356t-e071a887f7f7d9bf801c826eb911204ee4157d112fd1c805ac92ee1562eca3ba3</citedby><cites>FETCH-LOGICAL-c356t-e071a887f7f7d9bf801c826eb911204ee4157d112fd1c805ac92ee1562eca3ba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2017.01.001$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28129980$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jernigan, Finith E.</creatorcontrib><creatorcontrib>Hanai, Jun-ichi</creatorcontrib><creatorcontrib>Sukhatme, Vikas P.</creatorcontrib><creatorcontrib>Sun, Lijun</creatorcontrib><title>Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC50 of the most potent ACL inhibitor A1 is 4.1μM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer.</description><subject>ATP Citrate (pro-S)-Lyase - antagonists & inhibitors</subject><subject>ATP citrate lyase inhibitor</subject><subject>Cancer metabolism</subject><subject>Cancer stemness</subject><subject>Carboxylic Acids - chemistry</subject><subject>Carboxylic Acids - pharmacology</subject><subject>Cell Line</subject><subject>Drug Discovery</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Furans - chemistry</subject><subject>Furoic acid</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Structure</subject><subject>Virtual screening</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>eNp9kM1q3DAURkVJaaZpX6CLoGU2dnU1si1DNiH9SSDQLlLoTsjy9ViDx5pIsqnfvjKTZBmE0AWd74N7CPkCLAcG5dd93hzMkHMGVc4gZwzekQ2IUmRbwYozsmF1yTJZi7_n5GMI-wQIJsQHcs4l8LqWbEOWbzYYN6NfqOtoN3k9UqN94_4tg45IW_R21tHOGKgOdEzoQO3Y28ZG58Maunn8nRkb_YoPiw5IZ6vT9XHSA-3trs9i7920649TpMF4xNGOu0_kfaeHgJ-f3wvy58f3x9u77OHXz_vbm4fMbIsyZsgq0FJWXTpt3XSSgZG8xKYG4EwgCiiqNs1dmz5YoU3NEaEoORq9bfT2glydeo_ePU0YojqklXEY9IhuCgpkyauSS14nlJ9Q410IHjt19Pag_aKAqVW52qtVuVqVKwYqGU2hy-f-qTlg-xp5cZyA6xOAacvZolfBWBwNttajiap19q3-_w4glP0</recordid><startdate>20170215</startdate><enddate>20170215</enddate><creator>Jernigan, Finith E.</creator><creator>Hanai, Jun-ichi</creator><creator>Sukhatme, Vikas P.</creator><creator>Sun, Lijun</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></search><sort><creationdate>20170215</creationdate><title>Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening</title><author>Jernigan, Finith E. ; Hanai, Jun-ichi ; Sukhatme, Vikas P. ; Sun, Lijun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-e071a887f7f7d9bf801c826eb911204ee4157d112fd1c805ac92ee1562eca3ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>ATP Citrate (pro-S)-Lyase - antagonists & inhibitors</topic><topic>ATP citrate lyase inhibitor</topic><topic>Cancer metabolism</topic><topic>Cancer stemness</topic><topic>Carboxylic Acids - chemistry</topic><topic>Carboxylic Acids - pharmacology</topic><topic>Cell Line</topic><topic>Drug Discovery</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Furans - chemistry</topic><topic>Furoic acid</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Structure</topic><topic>Virtual screening</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jernigan, Finith E.</creatorcontrib><creatorcontrib>Hanai, Jun-ichi</creatorcontrib><creatorcontrib>Sukhatme, Vikas P.</creatorcontrib><creatorcontrib>Sun, Lijun</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jernigan, Finith E.</au><au>Hanai, Jun-ichi</au><au>Sukhatme, Vikas P.</au><au>Sun, Lijun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-02-15</date><risdate>2017</risdate><volume>27</volume><issue>4</issue><spage>929</spage><epage>935</epage><pages>929-935</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The enzyme ATP citrate lyase (ACL) catalyzes the formation of cytosolic acetyl CoA, the starting material for de novo lipid and cholesterol biosynthesis. The dysfunction and upregulation of ACL in numerous cancers makes it an attractive target for developing anticancer therapies. ACL inhibition by shRNA knockdown limits cancer cell proliferation and reduces cancer stemness. We designed and implemented a dual docking protocol to select virtual ACL inhibitors that were scored among the top 10 percentiles by both the Autodock Vina and the Glamdock algorithms. Via this in silico screens of a focused furoic acid library, we discovered four subtypes of furans and benzofurans as novel ACL inhibitors. The hit rate of our in silico protocol was 45.8% with 11 of 24 virtual hits confirmed as active in an in vitro ACL enzymatic assay. The IC50 of the most potent ACL inhibitor A1 is 4.1μM. Our results demonstrated remarkable hit rate by the dual docking approach and provided novel chemical scaffolds for the development of ACL inhibitors for the treatment of cancer.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28129980</pmid><doi>10.1016/j.bmcl.2017.01.001</doi><tpages>7</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2017-02, Vol.27 (4), p.929-935 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1862762829 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | ATP Citrate (pro-S)-Lyase - antagonists & inhibitors ATP citrate lyase inhibitor Cancer metabolism Cancer stemness Carboxylic Acids - chemistry Carboxylic Acids - pharmacology Cell Line Drug Discovery Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Furans - chemistry Furoic acid High-Throughput Screening Assays Humans Molecular Docking Simulation Molecular Structure Virtual screening |
| title | Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T14%3A21%3A23IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20furan%20carboxylate%20derivatives%20as%20novel%20inhibitors%20of%20ATP-citrate%20lyase%20via%20virtual%20high-throughput%20screening&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry%20letters&rft.au=Jernigan,%20Finith%20E.&rft.date=2017-02-15&rft.volume=27&rft.issue=4&rft.spage=929&rft.epage=935&rft.pages=929-935&rft.issn=0960-894X&rft.eissn=1464-3405&rft_id=info:doi/10.1016/j.bmcl.2017.01.001&rft_dat=%3Cproquest_cross%3E1862762829%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1862762829&rft_id=info:pmid/28129980&rft_els_id=S0960894X1730001X&rfr_iscdi=true |