Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease
Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington’s dise...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-02, Vol.55 (3), p.1021-1046 |
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| creator | Prime, Michael E Andersen, Ole A Barker, John J Brooks, Mark A Cheng, Robert K. Y Toogood-Johnson, Ian Courtney, Stephen M Brookfield, Frederick A Yarnold, Christopher J Marston, Richard W Johnson, Peter D Johnsen, Siw F Palfrey, Jordan J Vaidya, Darshan Erfan, Sayeh Ichihara, Osamu Felicetti, Brunella Palan, Shilpa Pedret-Dunn, Anna Schaertl, Sabine Sternberger, Ina Ebneth, Andreas Scheel, Andreas Winkler, Dirk Toledo-Sherman, Leticia Beconi, Maria Macdonald, Douglas Muñoz-Sanjuan, Ignacio Dominguez, Celia Wityak, John |
| description | Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington’s disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay. |
| doi_str_mv | 10.1021/jm201310y |
| format | Article |
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Y ; Toogood-Johnson, Ian ; Courtney, Stephen M ; Brookfield, Frederick A ; Yarnold, Christopher J ; Marston, Richard W ; Johnson, Peter D ; Johnsen, Siw F ; Palfrey, Jordan J ; Vaidya, Darshan ; Erfan, Sayeh ; Ichihara, Osamu ; Felicetti, Brunella ; Palan, Shilpa ; Pedret-Dunn, Anna ; Schaertl, Sabine ; Sternberger, Ina ; Ebneth, Andreas ; Scheel, Andreas ; Winkler, Dirk ; Toledo-Sherman, Leticia ; Beconi, Maria ; Macdonald, Douglas ; Muñoz-Sanjuan, Ignacio ; Dominguez, Celia ; Wityak, John</creator><creatorcontrib>Prime, Michael E ; Andersen, Ole A ; Barker, John J ; Brooks, Mark A ; Cheng, Robert K. 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Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. 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Y</creatorcontrib><creatorcontrib>Toogood-Johnson, Ian</creatorcontrib><creatorcontrib>Courtney, Stephen M</creatorcontrib><creatorcontrib>Brookfield, Frederick A</creatorcontrib><creatorcontrib>Yarnold, Christopher J</creatorcontrib><creatorcontrib>Marston, Richard W</creatorcontrib><creatorcontrib>Johnson, Peter D</creatorcontrib><creatorcontrib>Johnsen, Siw F</creatorcontrib><creatorcontrib>Palfrey, Jordan J</creatorcontrib><creatorcontrib>Vaidya, Darshan</creatorcontrib><creatorcontrib>Erfan, Sayeh</creatorcontrib><creatorcontrib>Ichihara, Osamu</creatorcontrib><creatorcontrib>Felicetti, Brunella</creatorcontrib><creatorcontrib>Palan, Shilpa</creatorcontrib><creatorcontrib>Pedret-Dunn, Anna</creatorcontrib><creatorcontrib>Schaertl, Sabine</creatorcontrib><creatorcontrib>Sternberger, Ina</creatorcontrib><creatorcontrib>Ebneth, Andreas</creatorcontrib><creatorcontrib>Scheel, Andreas</creatorcontrib><creatorcontrib>Winkler, Dirk</creatorcontrib><creatorcontrib>Toledo-Sherman, Leticia</creatorcontrib><creatorcontrib>Beconi, Maria</creatorcontrib><creatorcontrib>Macdonald, Douglas</creatorcontrib><creatorcontrib>Muñoz-Sanjuan, Ignacio</creatorcontrib><creatorcontrib>Dominguez, Celia</creatorcontrib><creatorcontrib>Wityak, John</creatorcontrib><title>Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington’s disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. 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Y ; Toogood-Johnson, Ian ; Courtney, Stephen M ; Brookfield, Frederick A ; Yarnold, Christopher J ; Marston, Richard W ; Johnson, Peter D ; Johnsen, Siw F ; Palfrey, Jordan J ; Vaidya, Darshan ; Erfan, Sayeh ; Ichihara, Osamu ; Felicetti, Brunella ; Palan, Shilpa ; Pedret-Dunn, Anna ; Schaertl, Sabine ; Sternberger, Ina ; Ebneth, Andreas ; Scheel, Andreas ; Winkler, Dirk ; Toledo-Sherman, Leticia ; Beconi, Maria ; Macdonald, Douglas ; Muñoz-Sanjuan, Ignacio ; Dominguez, Celia ; Wityak, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a380t-66a62919e9eefcde5e68e21ff6ac69ffc8ea4e668c153648ee8d517167aafde13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Acrylamides - chemical synthesis</topic><topic>Acrylamides - chemistry</topic><topic>Acrylamides - pharmacology</topic><topic>Animals</topic><topic>Caco-2 Cells</topic><topic>Cell Membrane Permeability</topic><topic>GTP-Binding Proteins - antagonists & inhibitors</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Huntington Disease - drug therapy</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Models, Molecular</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacology</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>Transglutaminases - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Prime, Michael E</creatorcontrib><creatorcontrib>Andersen, Ole A</creatorcontrib><creatorcontrib>Barker, John J</creatorcontrib><creatorcontrib>Brooks, Mark A</creatorcontrib><creatorcontrib>Cheng, Robert K. 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Y</au><au>Toogood-Johnson, Ian</au><au>Courtney, Stephen M</au><au>Brookfield, Frederick A</au><au>Yarnold, Christopher J</au><au>Marston, Richard W</au><au>Johnson, Peter D</au><au>Johnsen, Siw F</au><au>Palfrey, Jordan J</au><au>Vaidya, Darshan</au><au>Erfan, Sayeh</au><au>Ichihara, Osamu</au><au>Felicetti, Brunella</au><au>Palan, Shilpa</au><au>Pedret-Dunn, Anna</au><au>Schaertl, Sabine</au><au>Sternberger, Ina</au><au>Ebneth, Andreas</au><au>Scheel, Andreas</au><au>Winkler, Dirk</au><au>Toledo-Sherman, Leticia</au><au>Beconi, Maria</au><au>Macdonald, Douglas</au><au>Muñoz-Sanjuan, Ignacio</au><au>Dominguez, Celia</au><au>Wityak, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-02-09</date><risdate>2012</risdate><volume>55</volume><issue>3</issue><spage>1021</spage><epage>1046</epage><pages>1021-1046</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Tissue transglutaminase 2 (TG2) is a multifunctional protein primarily known for its calcium-dependent enzymatic protein cross-linking activity via isopeptide bond formation between glutamine and lysine residues. TG2 overexpression and activity have been found to be associated with Huntington’s disease (HD); specifically, TG2 is up-regulated in the brains of HD patients and in animal models of the disease. Interestingly, genetic deletion of TG2 in two different HD mouse models, R6/1 and R6/2, results in improved phenotypes including a reduction in neuronal death and prolonged survival. Starting with phenylacrylamide screening hit 7d, we describe the SAR of this series leading to potent and selective TG2 inhibitors. The suitability of the compounds as in vitro tools to elucidate the biology of TG2 was demonstrated through mode of inhibition studies, characterization of druglike properties, and inhibition profiles in a cell lysate assay.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22224594</pmid><doi>10.1021/jm201310y</doi><tpages>26</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2012-02, Vol.55 (3), p.1021-1046 |
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| subjects | Acrylamides - chemical synthesis Acrylamides - chemistry Acrylamides - pharmacology Animals Caco-2 Cells Cell Membrane Permeability GTP-Binding Proteins - antagonists & inhibitors HEK293 Cells Humans Huntington Disease - drug therapy In Vitro Techniques Male Mice Microsomes, Liver - metabolism Models, Molecular Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Rats Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacology Transglutaminases - antagonists & inhibitors |
| title | Discovery and Structure–Activity Relationship of Potent and Selective Covalent Inhibitors of Transglutaminase 2 for Huntington’s Disease |
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