Synthesis of calboxamide-containing tranylcypromine analogues as LSD1 (KDM1A) inhibitors targeting acute myeloid Leukemia

Teresa Borrello, Maria, Benelkebir, Hanae, Lee, Adam, Hin Tam, Chak, Shafat, Manar, Rushworth, Stuart A., Bowles, Kristian M., Douglas, Leon, Duriez, Patrick J., Bailey, Sarah, Crabb, Simon J., Packham, Graham and Ganesan, A. (2021) Synthesis of calboxamide-containing tranylcypromine analogues as LSD1 (KDM1A) inhibitors targeting acute myeloid Leukemia. ChemMedChem, 16 (8). pp. 1316-1324. ISSN 1860-7179

[img] PDF (Accepted_Manuscript) - Accepted Version
Restricted to Repository staff only until 3 February 2022.

Download (447kB) | Request a copy


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
Faculty of Medicine and Health Sciences > Norwich Medical School
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 06 May 2021 23:58
Last Modified: 30 Sep 2021 16:20
DOI: 10.1002/cmdc.202000754

Actions (login required)

View Item View Item