Synthesis of Carboxamide‐Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

Abstract

In memory of the late Professor Maurizio Botta 1950-2019 for his generous friendship and his many outstanding scientific contributions to medicinal chemistry.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 submicromolar 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.

Induction of AML cell differentiation using HOXA9/DNA binding inhibitors as a potential therapeutic option for HOXA9‐dependent AML

“…Given that conventional chemotherapy is still the standard AML treatment, the need for new targeted therapies, especially against various AML subtypes like those involving HOXA9, remains imperative. Among the newly approved or evaluated treatments, 2 , 3 differentiation therapies have indeed proved effective in the clinic such as the mitochondrial protein IDH2 (isocitrate dehydrogenase‐2) inhibitor enasidenib (AG221, Celgene), 5 , 38 the IDH1 inhibitor Ivosidenib (AG‐120, Agios), 5 , 39 lysine‐specific demethylase 1 (LSD1) inhibitors 40 , 41 such as tranylcypromine and analogs 32 , 42 or ORY‐1001, 3 , 43 , 44 , 45 or the DOT1L inhibitor pinometostat (EPZ‐5676) 7 , 17 , 46 , 47 known to downregulate HOXA9 expression. 48 More recently the Menin/MLL inhibitor revumenib (SNDX‐5613) showed promising results against the HOXA9‐dependant MLL subtypes of AML, 6 , 49 but it also led to resistance.…”

LSD1 inhibitors for cancer treatment: Focus on multi-target agents and compounds in clinical trials

“…In 2021, novel TCP analogues with a carboxamide at the para position of the benzene ring were developed by Borrello et al . Some of them, containing a benzyl-, 2-phenethyl-, or 2-thienylethylamino carboxamide portion ( 10a-c ) ( Figure 4 ) were submicromolar inhibitors of the enzyme (10a: IC 50 10a = 0.3 µM; IC 50 10b = 0.4 µM; IC 50 10c = 0.6 µM) ( Teresa Borrello et al, 2021 ).…”