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Teresa Borrello, Maria, Benelkebir, Hanae, Lee, Adam, Hin Tam, Chak, Shafat, Manar, Rushworth, Stuart A., Bowles, Kristian M. 
ORCID: https://orcid.org/0000-0003-1334-4526, Douglas, Leon, Duriez, Patrick J., Bailey, Sarah, Crabb, Simon J., Packham, Graham and Ganesan, A.
(2021)
Synthesis of carboxamide-containing tranylcypromine analogues as LSD1 (KDM1A) inhibitors targeting acute myeloid leukemia.
ChemMedChem, 16 (8).
pp. 1316-1324.
ISSN 1860-7179
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Abstract
Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC 50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | fad-dependent enzymes,acute myeloid leukemia,enzyme inhibitors,epigenetics,histone demethylases,biochemistry,molecular medicine,pharmacology,drug discovery,pharmacology, toxicology and pharmaceutics(all),organic chemistry,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1303 |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 06 May 2021 23:58 |
| Last Modified: | 18 Jun 2026 18:58 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/79938 |
| DOI: | 10.1002/cmdc.202000754 |
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