Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A
Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (R)- and (S)-2-((2-chlorophenyl)(2-(piperi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2018-04, Vol.61 (7), p.3193-3208 |
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| creator | Horton, John R Liu, Xu Wu, Lizhen Zhang, Kai Shanks, John Zhang, Xing Rai, Ganesha Mott, Bryan T Jansen, Daniel J Kales, Stephen C Henderson, Mark J Pohida, Katherine Fang, Yuhong Hu, Xin Jadhav, Ajit Maloney, David J Hall, Matthew D Simeonov, Anton Fu, Haian Vertino, Paula M Yan, Qin Cheng, Xiaodong |
| description | Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55). In vitro, the S enantiomer of the N51/N52 pair (N52) and the R enantiomer of the N54/N55 pair (N54) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the R-isoform for the cell-permeable N54/N55 pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family. |
| doi_str_mv | 10.1021/acs.jmedchem.8b00261 |
| format | Article |
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(ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55). In vitro, the S enantiomer of the N51/N52 pair (N52) and the R enantiomer of the N54/N55 pair (N54) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the R-isoform for the cell-permeable N54/N55 pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family.</description><identifier>ISSN: 0022-2623</identifier><identifier>ISSN: 1520-4804</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.8b00261</identifier><identifier>PMID: 29537847</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amides - chemistry ; Amides - pharmacology ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cell Membrane Permeability ; Cyclopropanes - chemistry ; Cyclopropanes - pharmacology ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Humans ; Models, Molecular ; Molecular Conformation ; Pyridines - chemical synthesis ; Pyridines - pharmacology ; Retinoblastoma-Binding Protein 2 - antagonists & inhibitors ; Stereoisomerism ; Structure-Activity Relationship ; Tumor Stem Cell Assay</subject><ispartof>Journal of medicinal chemistry, 2018-04, Vol.61 (7), p.3193-3208</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a476t-76c8b5c6392b7affc7024e031ae093de51fb81f3d65a7027401d7bce3626173</citedby><cites>FETCH-LOGICAL-a476t-76c8b5c6392b7affc7024e031ae093de51fb81f3d65a7027401d7bce3626173</cites><orcidid>0000-0002-6967-6362 ; 0000-0002-5073-442X ; 0000-0002-5607-4178 ; 0000-0001-9763-9641 ; 0000000256074178 ; 000000025073442X ; 0000000197639641 ; 0000000269676362</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.8b00261$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.8b00261$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29537847$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1463713$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Horton, John R</creatorcontrib><creatorcontrib>Liu, Xu</creatorcontrib><creatorcontrib>Wu, Lizhen</creatorcontrib><creatorcontrib>Zhang, Kai</creatorcontrib><creatorcontrib>Shanks, John</creatorcontrib><creatorcontrib>Zhang, Xing</creatorcontrib><creatorcontrib>Rai, Ganesha</creatorcontrib><creatorcontrib>Mott, Bryan T</creatorcontrib><creatorcontrib>Jansen, Daniel J</creatorcontrib><creatorcontrib>Kales, Stephen C</creatorcontrib><creatorcontrib>Henderson, Mark J</creatorcontrib><creatorcontrib>Pohida, Katherine</creatorcontrib><creatorcontrib>Fang, Yuhong</creatorcontrib><creatorcontrib>Hu, Xin</creatorcontrib><creatorcontrib>Jadhav, Ajit</creatorcontrib><creatorcontrib>Maloney, David J</creatorcontrib><creatorcontrib>Hall, Matthew D</creatorcontrib><creatorcontrib>Simeonov, Anton</creatorcontrib><creatorcontrib>Fu, Haian</creatorcontrib><creatorcontrib>Vertino, Paula M</creatorcontrib><creatorcontrib>Yan, Qin</creatorcontrib><creatorcontrib>Cheng, Xiaodong</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55). In vitro, the S enantiomer of the N51/N52 pair (N52) and the R enantiomer of the N54/N55 pair (N54) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the R-isoform for the cell-permeable N54/N55 pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family.</description><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Membrane Permeability</subject><subject>Cyclopropanes - chemistry</subject><subject>Cyclopropanes - pharmacology</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - pharmacology</subject><subject>Retinoblastoma-Binding Protein 2 - antagonists & inhibitors</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Stem Cell Assay</subject><issn>0022-2623</issn><issn>1520-4804</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UU1rGzEQFaWlcT7-QSmip17W1deu1peCSZPGYMghhR6FVp71KuxKqUYO-N9Xrp3QXnoamHnvzcx7hHzgbM6Z4F-sw_njBBs3wDRvO8ZEw9-QGa8Fq1TL1FsyKz1RiUbIM3KO-MgYk1zI9-RMLGqpW6Vn5OcqoN8OGakPOdI8AF267GOgsaerMPjO55joTbChdCdISO3W-oCZ3nnMMQBd79GX8g0myMN-tAi0Xl6Sd70dEa5O9YI83N78uL6r1vffV9fLdWWVbnKlG9d2tWvkQnTa9r3TTCgoZ1pgC7mBmvddy3u5aWpbRloxvtGdA9mUb7W8IF-Pqk-77mAFhJzsaJ6Sn2zam2i9-XcS_GC28dk0UgjFeRH4dBSImL1B5zO4wcUQwGXDVSM1lwX0-bQlxV87wGwmjw7G0QaIOzSCccVlsfSgp45QlyJigv71Fs7MITZTYjMvsZlTbIX28e8_XkkvORUAOwL-0OMuhWLq_zV_Ay2Qp90</recordid><startdate>20180412</startdate><enddate>20180412</enddate><creator>Horton, John R</creator><creator>Liu, Xu</creator><creator>Wu, Lizhen</creator><creator>Zhang, Kai</creator><creator>Shanks, John</creator><creator>Zhang, Xing</creator><creator>Rai, Ganesha</creator><creator>Mott, Bryan T</creator><creator>Jansen, Daniel J</creator><creator>Kales, Stephen C</creator><creator>Henderson, Mark J</creator><creator>Pohida, Katherine</creator><creator>Fang, Yuhong</creator><creator>Hu, Xin</creator><creator>Jadhav, Ajit</creator><creator>Maloney, David J</creator><creator>Hall, Matthew D</creator><creator>Simeonov, Anton</creator><creator>Fu, Haian</creator><creator>Vertino, Paula M</creator><creator>Yan, Qin</creator><creator>Cheng, Xiaodong</creator><general>American Chemical Society</general><general>American Chemical Society (ACS)</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>OTOTI</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6967-6362</orcidid><orcidid>https://orcid.org/0000-0002-5073-442X</orcidid><orcidid>https://orcid.org/0000-0002-5607-4178</orcidid><orcidid>https://orcid.org/0000-0001-9763-9641</orcidid><orcidid>https://orcid.org/0000000256074178</orcidid><orcidid>https://orcid.org/000000025073442X</orcidid><orcidid>https://orcid.org/0000000197639641</orcidid><orcidid>https://orcid.org/0000000269676362</orcidid></search><sort><creationdate>20180412</creationdate><title>Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A</title><author>Horton, John R ; Liu, Xu ; Wu, Lizhen ; Zhang, Kai ; Shanks, John ; Zhang, Xing ; Rai, Ganesha ; Mott, Bryan T ; Jansen, Daniel J ; Kales, Stephen C ; Henderson, Mark J ; Pohida, Katherine ; Fang, Yuhong ; Hu, Xin ; Jadhav, Ajit ; Maloney, David J ; Hall, Matthew D ; Simeonov, Anton ; Fu, Haian ; Vertino, Paula M ; Yan, Qin ; Cheng, Xiaodong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a476t-76c8b5c6392b7affc7024e031ae093de51fb81f3d65a7027401d7bce3626173</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Cell Line, Tumor</topic><topic>Cell Membrane Permeability</topic><topic>Cyclopropanes - chemistry</topic><topic>Cyclopropanes - pharmacology</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacology</topic><topic>Retinoblastoma-Binding Protein 2 - antagonists & inhibitors</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Stem Cell Assay</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Horton, John R</creatorcontrib><creatorcontrib>Liu, Xu</creatorcontrib><creatorcontrib>Wu, Lizhen</creatorcontrib><creatorcontrib>Zhang, Kai</creatorcontrib><creatorcontrib>Shanks, John</creatorcontrib><creatorcontrib>Zhang, Xing</creatorcontrib><creatorcontrib>Rai, Ganesha</creatorcontrib><creatorcontrib>Mott, Bryan T</creatorcontrib><creatorcontrib>Jansen, Daniel J</creatorcontrib><creatorcontrib>Kales, Stephen C</creatorcontrib><creatorcontrib>Henderson, Mark J</creatorcontrib><creatorcontrib>Pohida, Katherine</creatorcontrib><creatorcontrib>Fang, Yuhong</creatorcontrib><creatorcontrib>Hu, Xin</creatorcontrib><creatorcontrib>Jadhav, Ajit</creatorcontrib><creatorcontrib>Maloney, David J</creatorcontrib><creatorcontrib>Hall, Matthew D</creatorcontrib><creatorcontrib>Simeonov, Anton</creatorcontrib><creatorcontrib>Fu, Haian</creatorcontrib><creatorcontrib>Vertino, Paula M</creatorcontrib><creatorcontrib>Yan, Qin</creatorcontrib><creatorcontrib>Cheng, Xiaodong</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</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>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Horton, John R</au><au>Liu, Xu</au><au>Wu, Lizhen</au><au>Zhang, Kai</au><au>Shanks, John</au><au>Zhang, Xing</au><au>Rai, Ganesha</au><au>Mott, Bryan T</au><au>Jansen, Daniel J</au><au>Kales, Stephen C</au><au>Henderson, Mark J</au><au>Pohida, Katherine</au><au>Fang, Yuhong</au><au>Hu, Xin</au><au>Jadhav, Ajit</au><au>Maloney, David J</au><au>Hall, Matthew D</au><au>Simeonov, Anton</au><au>Fu, Haian</au><au>Vertino, Paula M</au><au>Yan, Qin</au><au>Cheng, Xiaodong</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2018-04-12</date><risdate>2018</risdate><volume>61</volume><issue>7</issue><spage>3193</spage><epage>3208</epage><pages>3193-3208</pages><issn>0022-2623</issn><issn>1520-4804</issn><eissn>1520-4804</eissn><abstract>Isomers of chiral drugs can exhibit marked differences in biological activities. We studied the binding and inhibitory activities of 12 compounds against KDM5A. Among them are two pairs of enantiomers representing two distinct inhibitor chemotypes, namely, (R)- and (S)-2-((2-chlorophenyl)(2-(piperidin-1-yl)ethoxy)methyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylic acid (compounds N51 and N52) and (R)- and (S)-N-(1-(3-isopropyl-1H-pyrazole-5-carbonyl)pyrrolidin-3-yl)cyclopropanecarboxamide (compounds N54 and N55). In vitro, the S enantiomer of the N51/N52 pair (N52) and the R enantiomer of the N54/N55 pair (N54) exhibited about 4- to 5-fold greater binding affinity. The more potent enzyme inhibition of KDM5A by the R-isoform for the cell-permeable N54/N55 pair translated to differences in growth inhibitory activity. We determined structures of the KDM5A catalytic domain in complex with all 12 inhibitors, which revealed the interactions (or lack thereof) responsible for the differences in binding affinity. These results provide insights to guide improvements in binding potency and avenues for development of cell permeable inhibitors of the KDM5 family.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>29537847</pmid><doi>10.1021/acs.jmedchem.8b00261</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-6967-6362</orcidid><orcidid>https://orcid.org/0000-0002-5073-442X</orcidid><orcidid>https://orcid.org/0000-0002-5607-4178</orcidid><orcidid>https://orcid.org/0000-0001-9763-9641</orcidid><orcidid>https://orcid.org/0000000256074178</orcidid><orcidid>https://orcid.org/000000025073442X</orcidid><orcidid>https://orcid.org/0000000197639641</orcidid><orcidid>https://orcid.org/0000000269676362</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amides - chemistry Amides - pharmacology Antineoplastic Agents - chemical synthesis Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Membrane Permeability Cyclopropanes - chemistry Cyclopropanes - pharmacology Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Humans Models, Molecular Molecular Conformation Pyridines - chemical synthesis Pyridines - pharmacology Retinoblastoma-Binding Protein 2 - antagonists & inhibitors Stereoisomerism Structure-Activity Relationship Tumor Stem Cell Assay |
| title | Insights into the Action of Inhibitor Enantiomers against Histone Lysine Demethylase 5A |
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