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Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7
Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the...
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
John Wiley and Sons Inc.
2017
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725665/ https://www.ncbi.nlm.nih.gov/pubmed/28976073 http://dx.doi.org/10.1002/anie.201706788 |
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| author | Gerken, Philip A. Wolstenhulme, Jamie R. Tumber, Anthony Hatch, Stephanie B. Zhang, Yijia Müller, Susanne Chandler, Shane A. Mair, Barbara Li, Fengling Nijman, Sebastian M. B. Konietzny, Rebecca Szommer, Tamas Yapp, Clarence Fedorov, Oleg Benesch, Justin L. P. Vedadi, Masoud Kessler, Benedikt M. Kawamura, Akane Brennan, Paul E. Smith, Martin D. |
| author_facet | Gerken, Philip A. Wolstenhulme, Jamie R. Tumber, Anthony Hatch, Stephanie B. Zhang, Yijia Müller, Susanne Chandler, Shane A. Mair, Barbara Li, Fengling Nijman, Sebastian M. B. Konietzny, Rebecca Szommer, Tamas Yapp, Clarence Fedorov, Oleg Benesch, Justin L. P. Vedadi, Masoud Kessler, Benedikt M. Kawamura, Akane Brennan, Paul E. Smith, Martin D. |
| author_sort | Gerken, Philip A. |
| collection | PubMed |
| description | Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations. |
| format | Online Article Text |
| id | pubmed-5725665 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2017 |
| publisher | John Wiley and Sons Inc. |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-57256652017-12-12 Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 Gerken, Philip A. Wolstenhulme, Jamie R. Tumber, Anthony Hatch, Stephanie B. Zhang, Yijia Müller, Susanne Chandler, Shane A. Mair, Barbara Li, Fengling Nijman, Sebastian M. B. Konietzny, Rebecca Szommer, Tamas Yapp, Clarence Fedorov, Oleg Benesch, Justin L. P. Vedadi, Masoud Kessler, Benedikt M. Kawamura, Akane Brennan, Paul E. Smith, Martin D. Angew Chem Int Ed Engl Communications Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell‐permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure–activity relationships, leading to the development of a small molecule with around 75‐fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations. John Wiley and Sons Inc. 2017-11-07 2017-12-04 /pmc/articles/PMC5725665/ /pubmed/28976073 http://dx.doi.org/10.1002/anie.201706788 Text en © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| spellingShingle | Communications Gerken, Philip A. Wolstenhulme, Jamie R. Tumber, Anthony Hatch, Stephanie B. Zhang, Yijia Müller, Susanne Chandler, Shane A. Mair, Barbara Li, Fengling Nijman, Sebastian M. B. Konietzny, Rebecca Szommer, Tamas Yapp, Clarence Fedorov, Oleg Benesch, Justin L. P. Vedadi, Masoud Kessler, Benedikt M. Kawamura, Akane Brennan, Paul E. Smith, Martin D. Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 |
| title | Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 |
| title_full | Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 |
| title_fullStr | Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 |
| title_full_unstemmed | Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 |
| title_short | Discovery of a Highly Selective Cell‐Active Inhibitor of the Histone Lysine Demethylases KDM2/7 |
| title_sort | discovery of a highly selective cell‐active inhibitor of the histone lysine demethylases kdm2/7 |
| topic | Communications |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725665/ https://www.ncbi.nlm.nih.gov/pubmed/28976073 http://dx.doi.org/10.1002/anie.201706788 |
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