Spurr, SS;
Bayle, ED;
Yu, W;
Li, F;
Tempel, W;
Vedadi, M;
Schapira, M;
(2016)
New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms.
Bioorganic & Medicinal Chemistry Letters
, 26
(18)
pp. 4518-4522.
10.1016/j.bmcl.2016.07.041.
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Abstract
A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.
| Type: | Article |
|---|---|
| Title: | New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bmcl.2016.07.041 |
| Publisher version: | http://dx.doi.org/10.1016/j.bmcl.2016.07.041 |
| Language: | English |
| Additional information: | Copyright © 2016 Elsevier Ltd. All rights reserved. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Chemistry, Medicinal, Chemistry, Organic, Pharmacology & Pharmacy, Chemistry, Protein methyltransferase, DOT1L inhibitors, Toyocamycin, Bioisostere, Cyano-deaza-SAH, H3K79 Methylation, Potent, Leukemia, Derivatives, Toyocamycin |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1508965 |
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