Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors.
<h4>Background</h4>Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε)-Methylation of lysine residues on histone tails is one of a number of post-translationa...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2010-11-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015535&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850133755323219968 |
|---|---|
| author | Oliver N F King Xuan Shirley Li Masaaki Sakurai Akane Kawamura Nathan R Rose Stanley S Ng Amy M Quinn Ganesha Rai Bryan T Mott Paul Beswick Robert J Klose Udo Oppermann Ajit Jadhav Tom D Heightman David J Maloney Christopher J Schofield Anton Simeonov |
| author_facet | Oliver N F King Xuan Shirley Li Masaaki Sakurai Akane Kawamura Nathan R Rose Stanley S Ng Amy M Quinn Ganesha Rai Bryan T Mott Paul Beswick Robert J Klose Udo Oppermann Ajit Jadhav Tom D Heightman David J Maloney Christopher J Schofield Anton Simeonov |
| author_sort | Oliver N F King |
| collection | DOAJ |
| description | <h4>Background</h4>Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε)-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.<h4>Principal findings</h4>High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4) family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II) and to modulate demethylation at the H3K9 locus in a cell-based assay.<h4>Conclusions</h4>These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation. |
| format | Article |
| id | doaj-art-7f1b6fc84c5540f9baf8ca08a18a0aa7 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2010-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-7f1b6fc84c5540f9baf8ca08a18a0aa72025-08-20T02:31:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-11-01511e1553510.1371/journal.pone.0015535Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors.Oliver N F KingXuan Shirley LiMasaaki SakuraiAkane KawamuraNathan R RoseStanley S NgAmy M QuinnGanesha RaiBryan T MottPaul BeswickRobert J KloseUdo OppermannAjit JadhavTom D HeightmanDavid J MaloneyChristopher J SchofieldAnton Simeonov<h4>Background</h4>Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N(ε)-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N(ε)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.<h4>Principal findings</h4>High-throughput screening of a ∼236,000-member collection of diverse molecules arrayed as dilution series was used to identify inhibitors of the JMJD2 (KDM4) family of 2-oxoglutarate-dependent histone demethylases. Initial screening hits were prioritized by a combination of cheminformatics, counterscreening using a coupled assay enzyme, and orthogonal confirmatory detection of inhibition by mass spectrometric assays. Follow-up studies were carried out on one of the series identified, 8-hydroxyquinolines, which were shown by crystallographic analyses to inhibit by binding to the active site Fe(II) and to modulate demethylation at the H3K9 locus in a cell-based assay.<h4>Conclusions</h4>These studies demonstrate that diverse compound screening can yield novel inhibitors of 2OG dependent histone demethylases and provide starting points for the development of potent and selective agents to interrogate epigenetic regulation.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015535&type=printable |
| spellingShingle | Oliver N F King Xuan Shirley Li Masaaki Sakurai Akane Kawamura Nathan R Rose Stanley S Ng Amy M Quinn Ganesha Rai Bryan T Mott Paul Beswick Robert J Klose Udo Oppermann Ajit Jadhav Tom D Heightman David J Maloney Christopher J Schofield Anton Simeonov Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. PLoS ONE |
| title | Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. |
| title_full | Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. |
| title_fullStr | Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. |
| title_full_unstemmed | Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. |
| title_short | Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors. |
| title_sort | quantitative high throughput screening identifies 8 hydroxyquinolines as cell active histone demethylase inhibitors |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0015535&type=printable |
| work_keys_str_mv | AT olivernfking quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT xuanshirleyli quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT masaakisakurai quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT akanekawamura quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT nathanrrose quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT stanleysng quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT amymquinn quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT ganesharai quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT bryantmott quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT paulbeswick quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT robertjklose quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT udooppermann quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT ajitjadhav quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT tomdheightman quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT davidjmaloney quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT christopherjschofield quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors AT antonsimeonov quantitativehighthroughputscreeningidentifies8hydroxyquinolinesascellactivehistonedemethylaseinhibitors |