Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition
Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinop...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2024-08, Vol.67 (15), p.12521-12533 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 12533 |
|---|---|
| container_issue | 15 |
| container_start_page | 12521 |
| container_title | Journal of medicinal chemistry |
| container_volume | 67 |
| creator | Ji, Jian’ai Jin, Yuhui Ma, Sinan Zhu, Yuxuan Bi, Xinyu You, Qidong Jiang, Zhengyu |
| description | Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel–Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury. |
| doi_str_mv | 10.1021/acs.jmedchem.4c00403 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3084766093</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3084766093</sourcerecordid><originalsourceid>FETCH-LOGICAL-a227t-7a85ec63cda182dfa1e3a8c8512846f78e57e96179ca8c7fe5a66e7df3f2088b3</originalsourceid><addsrcrecordid>eNp9kE9PAjEQxRujEUS_gTE9elmc_tltORIQJSFw0fOm253KkmWL7WLCt3cV8Ohpkpn33uT9CLlnMGTA2ZOxcbjZYmnXuB1KCyBBXJA-SzkkUoO8JH0AzhOecdEjNzFuAEAwLq5JT4xAKsZEnyynVbT-C8OBekcNXU5WY0mn-BFMiYE6H-jCFFWNdB58k0xxh02JTUtnGILftT5Wkc6bdVVUbeWbW3LlTB3x7jQH5H32_DZ5TRarl_lkvEgM56pNlNEp2kzY0jDNS2cYCqOtThnXMnNKY6pwlDE1st1aOUxNlqEqnXActC7EgDwec3fBf-4xtvm264F1bRr0-5gL0FJlGYxEJ5VHqQ0-xoAu34Vqa8IhZ5D_kMw7kvmZZH4i2dkeTh_2RXf7M53RdQI4Cn7tfh-arvD_md8JsoIR</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3084766093</pqid></control><display><type>article</type><title>Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Ji, Jian’ai ; Jin, Yuhui ; Ma, Sinan ; Zhu, Yuxuan ; Bi, Xinyu ; You, Qidong ; Jiang, Zhengyu</creator><creatorcontrib>Ji, Jian’ai ; Jin, Yuhui ; Ma, Sinan ; Zhu, Yuxuan ; Bi, Xinyu ; You, Qidong ; Jiang, Zhengyu</creatorcontrib><description>Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel–Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.4c00403</identifier><identifier>PMID: 39047113</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Drug Discovery ; Ferroptosis - drug effects ; Humans ; Iron - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Coactivators - antagonists & inhibitors ; Nuclear Receptor Coactivators - metabolism ; Peptides - chemistry ; Peptides - drug effects ; Peptides - metabolism</subject><ispartof>Journal of medicinal chemistry, 2024-08, Vol.67 (15), p.12521-12533</ispartof><rights>2024 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-a227t-7a85ec63cda182dfa1e3a8c8512846f78e57e96179ca8c7fe5a66e7df3f2088b3</cites><orcidid>0000-0002-8587-0122 ; 0000-0002-1671-1582</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.4c00403$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00403$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39047113$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ji, Jian’ai</creatorcontrib><creatorcontrib>Jin, Yuhui</creatorcontrib><creatorcontrib>Ma, Sinan</creatorcontrib><creatorcontrib>Zhu, Yuxuan</creatorcontrib><creatorcontrib>Bi, Xinyu</creatorcontrib><creatorcontrib>You, Qidong</creatorcontrib><creatorcontrib>Jiang, Zhengyu</creatorcontrib><title>Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel–Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.</description><subject>Animals</subject><subject>Drug Discovery</subject><subject>Ferroptosis - drug effects</subject><subject>Humans</subject><subject>Iron - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nuclear Receptor Coactivators - antagonists & inhibitors</subject><subject>Nuclear Receptor Coactivators - metabolism</subject><subject>Peptides - chemistry</subject><subject>Peptides - drug effects</subject><subject>Peptides - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE9PAjEQxRujEUS_gTE9elmc_tltORIQJSFw0fOm253KkmWL7WLCt3cV8Ohpkpn33uT9CLlnMGTA2ZOxcbjZYmnXuB1KCyBBXJA-SzkkUoO8JH0AzhOecdEjNzFuAEAwLq5JT4xAKsZEnyynVbT-C8OBekcNXU5WY0mn-BFMiYE6H-jCFFWNdB58k0xxh02JTUtnGILftT5Wkc6bdVVUbeWbW3LlTB3x7jQH5H32_DZ5TRarl_lkvEgM56pNlNEp2kzY0jDNS2cYCqOtThnXMnNKY6pwlDE1st1aOUxNlqEqnXActC7EgDwec3fBf-4xtvm264F1bRr0-5gL0FJlGYxEJ5VHqQ0-xoAu34Vqa8IhZ5D_kMw7kvmZZH4i2dkeTh_2RXf7M53RdQI4Cn7tfh-arvD_md8JsoIR</recordid><startdate>20240808</startdate><enddate>20240808</enddate><creator>Ji, Jian’ai</creator><creator>Jin, Yuhui</creator><creator>Ma, Sinan</creator><creator>Zhu, Yuxuan</creator><creator>Bi, Xinyu</creator><creator>You, Qidong</creator><creator>Jiang, Zhengyu</creator><general>American Chemical Society</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><orcidid>https://orcid.org/0000-0002-8587-0122</orcidid><orcidid>https://orcid.org/0000-0002-1671-1582</orcidid></search><sort><creationdate>20240808</creationdate><title>Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition</title><author>Ji, Jian’ai ; Jin, Yuhui ; Ma, Sinan ; Zhu, Yuxuan ; Bi, Xinyu ; You, Qidong ; Jiang, Zhengyu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a227t-7a85ec63cda182dfa1e3a8c8512846f78e57e96179ca8c7fe5a66e7df3f2088b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Drug Discovery</topic><topic>Ferroptosis - drug effects</topic><topic>Humans</topic><topic>Iron - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nuclear Receptor Coactivators - antagonists & inhibitors</topic><topic>Nuclear Receptor Coactivators - metabolism</topic><topic>Peptides - chemistry</topic><topic>Peptides - drug effects</topic><topic>Peptides - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ji, Jian’ai</creatorcontrib><creatorcontrib>Jin, Yuhui</creatorcontrib><creatorcontrib>Ma, Sinan</creatorcontrib><creatorcontrib>Zhu, Yuxuan</creatorcontrib><creatorcontrib>Bi, Xinyu</creatorcontrib><creatorcontrib>You, Qidong</creatorcontrib><creatorcontrib>Jiang, Zhengyu</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ji, Jian’ai</au><au>Jin, Yuhui</au><au>Ma, Sinan</au><au>Zhu, Yuxuan</au><au>Bi, Xinyu</au><au>You, Qidong</au><au>Jiang, Zhengyu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-08-08</date><risdate>2024</risdate><volume>67</volume><issue>15</issue><spage>12521</spage><epage>12533</epage><pages>12521-12533</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Ferroptosis, a distinctive form of programmed cell death, has been implicated in numerous pathological conditions, and its inhibition is considered a promising therapeutic strategy. Currently, there is a scarcity of efficient antagonists for directly regulating intracellular ferrous iron. Ferritinophagy, an essential process for supplying intracellular labile iron, relies on nuclear receptor coactivator 4 (NCOA4), a selective autophagy receptor for the ferritin iron storage complex, thus playing a pivotal role in ferritinophagy. In this study, we reported a novel von Hippel–Lindau-based NCOA4 degrader, V3, as a potent ferroptosis inhibitor with an intracellular ferrous iron inhibition mechanism. V3 significantly reduced NCOA4 levels and downregulated intracellular ferrous iron (Fe2+) levels, thereby effectively suppressing ferroptosis induced by multiple pathways within cells and alleviating liver damage. This research presents a chemical knockdown tool targeting NCOA4 for further exploration into intracellular ferrous iron in ferroptosis, offering a promising therapeutic avenue for ferroptosis-related acute liver injury.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>39047113</pmid><doi>10.1021/acs.jmedchem.4c00403</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-8587-0122</orcidid><orcidid>https://orcid.org/0000-0002-1671-1582</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2024-08, Vol.67 (15), p.12521-12533 |
| issn | 0022-2623 1520-4804 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3084766093 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Drug Discovery Ferroptosis - drug effects Humans Iron - metabolism Male Mice Mice, Inbred C57BL Nuclear Receptor Coactivators - antagonists & inhibitors Nuclear Receptor Coactivators - metabolism Peptides - chemistry Peptides - drug effects Peptides - metabolism |
| title | Discovery of a NCOA4 Degrader for Labile Iron-Dependent Ferroptosis Inhibition |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-25T00%3A25%3A33IST&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%20a%20NCOA4%20Degrader%20for%20Labile%20Iron-Dependent%20Ferroptosis%20Inhibition&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Ji,%20Jian%E2%80%99ai&rft.date=2024-08-08&rft.volume=67&rft.issue=15&rft.spage=12521&rft.epage=12533&rft.pages=12521-12533&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.4c00403&rft_dat=%3Cproquest_cross%3E3084766093%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=3084766093&rft_id=info:pmid/39047113&rfr_iscdi=true |