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<dublin_core schema="dc">
<dcvalue element="contributor" qualifier="author">Hatcher,&#x20;John&#x20;M.</dcvalue>
<dcvalue element="contributor" qualifier="author">Wang,&#x20;Eric&#x20;S.</dcvalue>
<dcvalue element="contributor" qualifier="author">Johannessen,&#x20;Liv</dcvalue>
<dcvalue element="contributor" qualifier="author">Kwiatkowski,&#x20;Nicholas</dcvalue>
<dcvalue element="contributor" qualifier="author">Sim,&#x20;Taebo</dcvalue>
<dcvalue element="contributor" qualifier="author">Gray,&#x20;Nathanael&#x20;S.</dcvalue>
<dcvalue element="date" qualifier="accessioned">2024-01-19T22:33:25Z</dcvalue>
<dcvalue element="date" qualifier="available">2024-01-19T22:33:25Z</dcvalue>
<dcvalue element="date" qualifier="created">2021-09-03</dcvalue>
<dcvalue element="date" qualifier="issued">2018-06</dcvalue>
<dcvalue element="identifier" qualifier="issn">1948-5875</dcvalue>
<dcvalue element="identifier" qualifier="uri">https:&#x2F;&#x2F;pubs.kist.re.kr&#x2F;handle&#x2F;201004&#x2F;121320</dcvalue>
<dcvalue element="description" qualifier="abstract">Cortistatin&#x20;A&#x20;is&#x20;a&#x20;natural&#x20;product&#x20;isolated&#x20;from&#x20;the&#x20;marine&#x20;sponge&#x20;Corticium&#x20;simplex&#x20;and&#x20;was&#x20;found&#x20;to&#x20;be&#x20;a&#x20;potent&#x20;and&#x20;selective&#x20;inhibitor&#x20;of&#x20;CDK8.&#x20;Many&#x20;synthetic&#x20;groups&#x20;have&#x20;reported&#x20;total&#x20;syntheses&#x20;of&#x20;Cortistatin&#x20;A;&#x20;however,&#x20;these&#x20;syntheses&#x20;require&#x20;between&#x20;16&#x20;and&#x20;30&#x20;steps&#x20;and&#x20;report&#x20;between&#x20;0.012-2%&#x20;overall&#x20;yields,&#x20;which&#x20;is&#x20;not&#x20;amenable&#x20;to&#x20;large-scale&#x20;production.&#x20;Owing&#x20;to&#x20;similarities&#x20;between&#x20;the&#x20;complex&#x20;core&#x20;of&#x20;Cortistatin&#x20;A&#x20;and&#x20;the&#x20;simple&#x20;steroid&#x20;core,&#x20;we&#x20;initiated&#x20;a&#x20;campaign&#x20;to&#x20;design&#x20;simple,&#x20;more&#x20;easily&#x20;prepared&#x20;CDK8&#x20;inhibitors&#x20;based&#x20;on&#x20;a&#x20;steroid&#x20;scaffold&#x20;that&#x20;would&#x20;be&#x20;more&#x20;convenient&#x20;for&#x20;large-scale&#x20;synthesis.&#x20;Herein,&#x20;we&#x20;report&#x20;the&#x20;discovery&#x20;and&#x20;optimization&#x20;of&#x20;JH-VIII-49,&#x20;a&#x20;potent&#x20;and&#x20;selective&#x20;inhibitor&#x20;of&#x20;CDK8&#x20;with&#x20;a&#x20;simple&#x20;steroid&#x20;core&#x20;that&#x20;has&#x20;an&#x20;eight-step&#x20;synthesis&#x20;with&#x20;a&#x20;33%&#x20;overall&#x20;yield,&#x20;making&#x20;it&#x20;suitable&#x20;for&#x20;large-scale&#x20;preparation.&#x20;Using&#x20;this&#x20;scaffold,&#x20;we&#x20;then&#x20;developed&#x20;a&#x20;bivalent&#x20;small&#x20;molecule&#x20;degrader,&#x20;JH-XI-10-02,&#x20;that&#x20;can&#x20;recruit&#x20;the&#x20;E3&#x20;ligase&#x20;CRL4(cerebion)&#x20;to&#x20;promote&#x20;the&#x20;ubiquitination&#x20;and&#x20;proteosomal&#x20;degradation&#x20;of&#x20;CDK8.</dcvalue>
<dcvalue element="language" qualifier="none">English</dcvalue>
<dcvalue element="publisher" qualifier="none">AMER&#x20;CHEMICAL&#x20;SOC</dcvalue>
<dcvalue element="subject" qualifier="none">MEDIATOR&#x20;COMPLEX</dcvalue>
<dcvalue element="subject" qualifier="none">KINASE</dcvalue>
<dcvalue element="subject" qualifier="none">TRANSCRIPTION</dcvalue>
<dcvalue element="subject" qualifier="none">CORTISTATIN</dcvalue>
<dcvalue element="subject" qualifier="none">GENES</dcvalue>
<dcvalue element="subject" qualifier="none">DEGRADATION</dcvalue>
<dcvalue element="subject" qualifier="none">ELONGATION</dcvalue>
<dcvalue element="subject" qualifier="none">ACTIVATION</dcvalue>
<dcvalue element="subject" qualifier="none">SRB10&#x2F;CDK8</dcvalue>
<dcvalue element="subject" qualifier="none">TURNOVER</dcvalue>
<dcvalue element="title" qualifier="none">Development&#x20;of&#x20;Highly&#x20;Potent&#x20;and&#x20;Selective&#x20;Steroidal&#x20;Inhibitors&#x20;and&#x20;Degraders&#x20;of&#x20;CDK8</dcvalue>
<dcvalue element="type" qualifier="none">Article</dcvalue>
<dcvalue element="identifier" qualifier="doi">10.1021&#x2F;acsmedchemlett.8b00011</dcvalue>
<dcvalue element="description" qualifier="journalClass">1</dcvalue>
<dcvalue element="identifier" qualifier="bibliographicCitation">ACS&#x20;MEDICINAL&#x20;CHEMISTRY&#x20;LETTERS,&#x20;v.9,&#x20;no.6,&#x20;pp.540&#x20;-&#x20;545</dcvalue>
<dcvalue element="citation" qualifier="title">ACS&#x20;MEDICINAL&#x20;CHEMISTRY&#x20;LETTERS</dcvalue>
<dcvalue element="citation" qualifier="volume">9</dcvalue>
<dcvalue element="citation" qualifier="number">6</dcvalue>
<dcvalue element="citation" qualifier="startPage">540</dcvalue>
<dcvalue element="citation" qualifier="endPage">545</dcvalue>
<dcvalue element="description" qualifier="journalRegisteredClass">scie</dcvalue>
<dcvalue element="description" qualifier="journalRegisteredClass">scopus</dcvalue>
<dcvalue element="identifier" qualifier="wosid">000435613500006</dcvalue>
<dcvalue element="identifier" qualifier="scopusid">2-s2.0-85048541051</dcvalue>
<dcvalue element="relation" qualifier="journalWebOfScienceCategory">Chemistry,&#x20;Medicinal</dcvalue>
<dcvalue element="relation" qualifier="journalResearchArea">Pharmacology&#x20;&amp;&#x20;Pharmacy</dcvalue>
<dcvalue element="type" qualifier="docType">Article</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">MEDIATOR&#x20;COMPLEX</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">KINASE</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">TRANSCRIPTION</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">CORTISTATIN</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">GENES</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">DEGRADATION</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">ELONGATION</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">ACTIVATION</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">SRB10&#x2F;CDK8</dcvalue>
<dcvalue element="subject" qualifier="keywordPlus">TURNOVER</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">CDK8</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">CDK19</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">Cortistatin&#x20;A</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">kinase&#x20;inhibitor</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">mediator&#x20;complex</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">PROTAC</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">Cereblon</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">E3&#x20;ligase</dcvalue>
<dcvalue element="subject" qualifier="keywordAuthor">degradation</dcvalue>
</dublin_core>
