SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates
[Display omitted] The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigati...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2021-06, Vol.39, p.116141-116141, Article 116141 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Tiwari, Anand D. Guan, Yihong Grabowski, Dale R. Maciejewski, Jaroslaw P. Jha, Babal K. Phillips, James G. |
| description | [Display omitted]
The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigations described here is derived from the need to develop illuminating small molecule probes for TET enzymes with cellular activity and specificity. The studies were done so in the context of the importance of TET2 in the hematopoietic system and the preponderance of loss of function somatic TET2 mutations in myeloid diseases. We have identified that 2-hydroxy-4-methylene-pentanedicarboxylic acid 2a reversibly competes with the co-substrate α-KG in the TET2 catalytic domain and inhibits the dioxygenase activity with an IC50 = 11.0 ± 0.9 μM at 10 μM α-KG in a cell free system and binds in the TET2 catalytic domain with Kd = 0.3 ± 0.12 μM. |
| doi_str_mv | 10.1016/j.bmc.2021.116141 |
| format | Article |
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The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigations described here is derived from the need to develop illuminating small molecule probes for TET enzymes with cellular activity and specificity. The studies were done so in the context of the importance of TET2 in the hematopoietic system and the preponderance of loss of function somatic TET2 mutations in myeloid diseases. We have identified that 2-hydroxy-4-methylene-pentanedicarboxylic acid 2a reversibly competes with the co-substrate α-KG in the TET2 catalytic domain and inhibits the dioxygenase activity with an IC50 = 11.0 ± 0.9 μM at 10 μM α-KG in a cell free system and binds in the TET2 catalytic domain with Kd = 0.3 ± 0.12 μM.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2021.116141</identifier><identifier>PMID: 33894507</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>2-Hydroxyglutarate ; Catalytic Domain - drug effects ; Cell-Free System ; Dicarboxylic Acids - chemical synthesis ; Dicarboxylic Acids - chemistry ; Dicarboxylic Acids - pharmacology ; Dioxygenase ; Dioxygenases - metabolism ; DNA Methylation ; DNA-Binding Proteins - metabolism ; Enzyme inhibition ; Epigenetic ; Humans ; Molecular Docking Simulation ; Spectrum Analysis - methods ; Structure-Activity Relationship ; TET ; THP-1 Cells ; α-KG</subject><ispartof>Bioorganic & medicinal chemistry, 2021-06, Vol.39, p.116141-116141, Article 116141</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-c11dfa133040b1f0dcfe13ef1526cef37c15c1e110e639590d222709f8d6eef3</citedby><cites>FETCH-LOGICAL-c451t-c11dfa133040b1f0dcfe13ef1526cef37c15c1e110e639590d222709f8d6eef3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2021.116141$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33894507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tiwari, Anand D.</creatorcontrib><creatorcontrib>Guan, Yihong</creatorcontrib><creatorcontrib>Grabowski, Dale R.</creatorcontrib><creatorcontrib>Maciejewski, Jaroslaw P.</creatorcontrib><creatorcontrib>Jha, Babal K.</creatorcontrib><creatorcontrib>Phillips, James G.</creatorcontrib><title>SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigations described here is derived from the need to develop illuminating small molecule probes for TET enzymes with cellular activity and specificity. The studies were done so in the context of the importance of TET2 in the hematopoietic system and the preponderance of loss of function somatic TET2 mutations in myeloid diseases. We have identified that 2-hydroxy-4-methylene-pentanedicarboxylic acid 2a reversibly competes with the co-substrate α-KG in the TET2 catalytic domain and inhibits the dioxygenase activity with an IC50 = 11.0 ± 0.9 μM at 10 μM α-KG in a cell free system and binds in the TET2 catalytic domain with Kd = 0.3 ± 0.12 μM.</description><subject>2-Hydroxyglutarate</subject><subject>Catalytic Domain - drug effects</subject><subject>Cell-Free System</subject><subject>Dicarboxylic Acids - chemical synthesis</subject><subject>Dicarboxylic Acids - chemistry</subject><subject>Dicarboxylic Acids - pharmacology</subject><subject>Dioxygenase</subject><subject>Dioxygenases - metabolism</subject><subject>DNA Methylation</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enzyme inhibition</subject><subject>Epigenetic</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Spectrum Analysis - methods</subject><subject>Structure-Activity Relationship</subject><subject>TET</subject><subject>THP-1 Cells</subject><subject>α-KG</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU9r3DAQxUVpabZpP0AvxcdetNFI_ttCIYS0CSQEmr0LWRrFWmxrK2lD_O2rsEloLj2N4L15M5ofIZ-BrYFBfbJd95Nec8ZhDVBDCW_ICsq6pEJ08JasWFe3lLVdfUQ-xLhljPGyg_fkSIi2KyvWrMh4e_q7cHN0d0OK-ZF8sTnf8EKrpMYlOV0YPyk3Z2lwvUvOz9-K22VOA0YXC28LTi8WE_zDQkt6jWlYRpyR7nBOakbjtAp9FkeVMH4k76waI356qsdk8_N8c3ZBr25-XZ6dXlFdVpCoBjBWgRCsZD1YZrRFEGih4rVGKxoNlQYEYFiLruqY4Zw3rLOtqTHrx-THIXa37yc0Oq8S1Ch3wU0qLNIrJ18rsxvknb-XLTQAwHPA16eA4P_sMSY5uahxHPOP_D5KXkHLeduwNlvhYNXBxxjQvowBJh8hya3MkOQjJHmAlHu-_LvfS8czlWz4fjBgPtK9wyCjdjjrfM6AOknj3X_i_wIq6KRK</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Tiwari, Anand D.</creator><creator>Guan, Yihong</creator><creator>Grabowski, Dale R.</creator><creator>Maciejewski, Jaroslaw P.</creator><creator>Jha, Babal K.</creator><creator>Phillips, James G.</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>5PM</scope></search><sort><creationdate>20210601</creationdate><title>SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates</title><author>Tiwari, Anand D. ; Guan, Yihong ; Grabowski, Dale R. ; Maciejewski, Jaroslaw P. ; Jha, Babal K. ; Phillips, James G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-c11dfa133040b1f0dcfe13ef1526cef37c15c1e110e639590d222709f8d6eef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>2-Hydroxyglutarate</topic><topic>Catalytic Domain - drug effects</topic><topic>Cell-Free System</topic><topic>Dicarboxylic Acids - chemical synthesis</topic><topic>Dicarboxylic Acids - chemistry</topic><topic>Dicarboxylic Acids - pharmacology</topic><topic>Dioxygenase</topic><topic>Dioxygenases - metabolism</topic><topic>DNA Methylation</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enzyme inhibition</topic><topic>Epigenetic</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Spectrum Analysis - methods</topic><topic>Structure-Activity Relationship</topic><topic>TET</topic><topic>THP-1 Cells</topic><topic>α-KG</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tiwari, Anand D.</creatorcontrib><creatorcontrib>Guan, Yihong</creatorcontrib><creatorcontrib>Grabowski, Dale R.</creatorcontrib><creatorcontrib>Maciejewski, Jaroslaw P.</creatorcontrib><creatorcontrib>Jha, Babal K.</creatorcontrib><creatorcontrib>Phillips, James G.</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>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tiwari, Anand D.</au><au>Guan, Yihong</au><au>Grabowski, Dale R.</au><au>Maciejewski, Jaroslaw P.</au><au>Jha, Babal K.</au><au>Phillips, James G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>39</volume><spage>116141</spage><epage>116141</epage><pages>116141-116141</pages><artnum>116141</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
The TET (Ten-Eleven Translocation) dioxygenase enzyme family comprising 3 members, TET1-3, play key roles in DNA demethylation. These processes regulate transcription programs that determine cell lineage, survival, proliferation, and differentiation. The impetus for our investigations described here is derived from the need to develop illuminating small molecule probes for TET enzymes with cellular activity and specificity. The studies were done so in the context of the importance of TET2 in the hematopoietic system and the preponderance of loss of function somatic TET2 mutations in myeloid diseases. We have identified that 2-hydroxy-4-methylene-pentanedicarboxylic acid 2a reversibly competes with the co-substrate α-KG in the TET2 catalytic domain and inhibits the dioxygenase activity with an IC50 = 11.0 ± 0.9 μM at 10 μM α-KG in a cell free system and binds in the TET2 catalytic domain with Kd = 0.3 ± 0.12 μM.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33894507</pmid><doi>10.1016/j.bmc.2021.116141</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 2-Hydroxyglutarate Catalytic Domain - drug effects Cell-Free System Dicarboxylic Acids - chemical synthesis Dicarboxylic Acids - chemistry Dicarboxylic Acids - pharmacology Dioxygenase Dioxygenases - metabolism DNA Methylation DNA-Binding Proteins - metabolism Enzyme inhibition Epigenetic Humans Molecular Docking Simulation Spectrum Analysis - methods Structure-Activity Relationship TET THP-1 Cells α-KG |
| title | SAR insights into TET2 catalytic domain inhibition: Synthesis of 2-Hydroxy-4-Methylene-pentanedicarboxylates |
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