Synthesis of carboxamide-containing tranylcypromine analogues as LSD1 (KDM1A) inhibitors targeting acute myeloid leukemia

Maria Teresa Borrello, Hanae Benelkebir, Adam Lee, Chak Hin Tam, Manar Shafat, Stuart A. Rushworth, Kristian M. Bowles, Leon Douglas, Patrick J. Duriez, Sarah Bailey, Simon J. Crabb, Graham Packham, A. Ganesan

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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.

Original languageEnglish
Pages (from-to)1316-1324
Number of pages9
Issue number8
Early online date3 Feb 2021
Publication statusPublished - 20 Apr 2021


  • FAD-dependent enzymes
  • acute myeloid leukemia
  • enzyme inhibitors
  • epigenetics
  • histone demethylases

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