An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent
Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(iii) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex is able to antagonize the BRD4-acetylated histone protein-prote...
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| Veröffentlicht in: | Chemical science (Cambridge) 2015-10, Vol.6 (10), p.5400-5408 |
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| creator | Zhong, Hai-Jing Lu, Lihua Leung, Ka-Ho Wong, Catherine C L Peng, Chao Yan, Siu-Cheong Ma, Dik-Lung Cai, Zongwei David Wang, Hui-Min Leung, Chung-Hang |
| description | Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(iii) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex
is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI)
, and to bind BRD4 and down-regulate c-
oncogenic expression
. Chromatin immunoprecipitation (ChIP) analysis revealed that
could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an
mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex
may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma. |
| doi_str_mv | 10.1039/c5sc02321a |
| format | Article |
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is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI)
, and to bind BRD4 and down-regulate c-
oncogenic expression
. Chromatin immunoprecipitation (ChIP) analysis revealed that
could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an
mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex
may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.</description><identifier>ISSN: 2041-6520</identifier><identifier>EISSN: 2041-6539</identifier><identifier>DOI: 10.1039/c5sc02321a</identifier><identifier>PMID: 28757943</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Chemistry</subject><ispartof>Chemical science (Cambridge), 2015-10, Vol.6 (10), p.5400-5408</ispartof><rights>This journal is © The Royal Society of Chemistry 2015 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c444t-6cda5785d9ed1a5314baaa77f82d51ca10f848ef7e50b6c5ffd479dc6e136f733</citedby><cites>FETCH-LOGICAL-c444t-6cda5785d9ed1a5314baaa77f82d51ca10f848ef7e50b6c5ffd479dc6e136f733</cites><orcidid>0000-0002-9515-340X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510529/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510529/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28757943$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhong, Hai-Jing</creatorcontrib><creatorcontrib>Lu, Lihua</creatorcontrib><creatorcontrib>Leung, Ka-Ho</creatorcontrib><creatorcontrib>Wong, Catherine C L</creatorcontrib><creatorcontrib>Peng, Chao</creatorcontrib><creatorcontrib>Yan, Siu-Cheong</creatorcontrib><creatorcontrib>Ma, Dik-Lung</creatorcontrib><creatorcontrib>Cai, Zongwei</creatorcontrib><creatorcontrib>David Wang, Hui-Min</creatorcontrib><creatorcontrib>Leung, Chung-Hang</creatorcontrib><title>An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent</title><title>Chemical science (Cambridge)</title><addtitle>Chem Sci</addtitle><description>Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(iii) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex
is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI)
, and to bind BRD4 and down-regulate c-
oncogenic expression
. Chromatin immunoprecipitation (ChIP) analysis revealed that
could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an
mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex
may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.</description><subject>Chemistry</subject><issn>2041-6520</issn><issn>2041-6539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNpVkVtrFEEQhRtRTIh58QdIP0ZhtK_TMy_CuiYqBAQvz01Nd3VSMjO9ds8G_PdOzLpovVRR9XFOwWHsuRSvpdD9m2BrEEorCY_YqRJGNq3V_ePjrMQJO6_1h1hLa2mVe8pOVOes640-ZdNm5lQo0n66IKKXzQAV47oqeIel0jAi35W8IM3NoXOaFywQFsr38y0NtOTCc-Lvvrw3HCoHvlvJeeEwLxRgDlg43KyLZ-xJgrHi-aGfse9Xl9-2H5vrzx8-bTfXTTDGLE0bIljX2dhjlGC1NAMAOJc6Fa0MIEXqTIfJoRVDG2xK0bg-hhalbpPT-oy9fdDd7YcJY1itC4x-V2iC8stnIP__ZaZbf5PvvLVSWNWvAhcHgZJ_7rEufqIacBxhxryvXvbKdL12Vq7oqwc0lFxrwXS0kcLfR-S39uv2T0SbFX7x72NH9G8g-jf_j46z</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Zhong, Hai-Jing</creator><creator>Lu, Lihua</creator><creator>Leung, Ka-Ho</creator><creator>Wong, Catherine C L</creator><creator>Peng, Chao</creator><creator>Yan, Siu-Cheong</creator><creator>Ma, Dik-Lung</creator><creator>Cai, Zongwei</creator><creator>David Wang, Hui-Min</creator><creator>Leung, Chung-Hang</creator><general>Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9515-340X</orcidid></search><sort><creationdate>20151001</creationdate><title>An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent</title><author>Zhong, Hai-Jing ; Lu, Lihua ; Leung, Ka-Ho ; Wong, Catherine C L ; Peng, Chao ; Yan, Siu-Cheong ; Ma, Dik-Lung ; Cai, Zongwei ; David Wang, Hui-Min ; Leung, Chung-Hang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c444t-6cda5785d9ed1a5314baaa77f82d51ca10f848ef7e50b6c5ffd479dc6e136f733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhong, Hai-Jing</creatorcontrib><creatorcontrib>Lu, Lihua</creatorcontrib><creatorcontrib>Leung, Ka-Ho</creatorcontrib><creatorcontrib>Wong, Catherine C L</creatorcontrib><creatorcontrib>Peng, Chao</creatorcontrib><creatorcontrib>Yan, Siu-Cheong</creatorcontrib><creatorcontrib>Ma, Dik-Lung</creatorcontrib><creatorcontrib>Cai, Zongwei</creatorcontrib><creatorcontrib>David Wang, Hui-Min</creatorcontrib><creatorcontrib>Leung, Chung-Hang</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemical science (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhong, Hai-Jing</au><au>Lu, Lihua</au><au>Leung, Ka-Ho</au><au>Wong, Catherine C L</au><au>Peng, Chao</au><au>Yan, Siu-Cheong</au><au>Ma, Dik-Lung</au><au>Cai, Zongwei</au><au>David Wang, Hui-Min</au><au>Leung, Chung-Hang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent</atitle><jtitle>Chemical science (Cambridge)</jtitle><addtitle>Chem Sci</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>6</volume><issue>10</issue><spage>5400</spage><epage>5408</epage><pages>5400-5408</pages><issn>2041-6520</issn><eissn>2041-6539</eissn><abstract>Bromodomain-containing protein 4 (BRD4) has recently emerged as an attractive epigenetic target for anticancer therapy. In this study, an iridium(iii) complex is reported as the first metal-based, irreversible inhibitor of BRD4. Complex
is able to antagonize the BRD4-acetylated histone protein-protein interaction (PPI)
, and to bind BRD4 and down-regulate c-
oncogenic expression
. Chromatin immunoprecipitation (ChIP) analysis revealed that
could modulate the interaction between BRD4 and chromatin in melanoma cells, particular at the MYC promoter. Finally, the complex showed potent activity against melanoma xenografts in an
mouse model. To our knowledge, this is the first report of a Group 9 metal complex inhibiting the PPI of a member of the bromodomain and extraterminal domain (BET) family. We envision that complex
may serve as a useful scaffold for the development of more potent epigenetic agents against cancers such as melanoma.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>28757943</pmid><doi>10.1039/c5sc02321a</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-9515-340X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Chemistry |
| title | An iridium(iii)-based irreversible protein-protein interaction inhibitor of BRD4 as a potent anticancer agent |
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