Synthesis of Carboxamide‐Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia. (3rd February 2021)

• Record Type: Journal Article
• Authors: 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; Ganesan, A.
• Is Part Of: ChemMedChem. Volume 16:Number 8(2021)
• Page Start: 1316
• Page End: 1324
• Publication Date: 2021-02-03
• Subjects: acute myeloid leukemia -- enzyme inhibitors -- epigenetics -- FAD-dependent enzymes -- histone demethylases; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000754
• Languages: English
• ISSNs: 1860-7179

Abstract

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 IC50 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. Abstract : Para ‐chuting in on cancer : Second‐generation tranylcypromine analogues containing a para ‐carboxamide substituent in the phenyl ring potently inhibit the LSD1 demethylase and a panel of AML cell lines. Carbamate derivatives were inactive against the enzyme but retained cellular potency, thus suggesting a prodrug mechanism.