Histone lysine specific demethylase 1 inhibitors

Abstract

LSD1 plays a pivotal role in numerous biological functions.

N-Methylpropargylamine-Conjugated Hydroxamic Acids as Dual Inhibitors of Monoamine Oxidase A and Histone Deacetylase for Glioma Treatment

“…7-{2-Chloro-3-[3-(methyl-prop-2-ynyl-amino)-propoxy]-phenyl-carbamoyl}-heptanoic Acid Methyl Ester (33). Compound 33 was synthesized using 29 (0.3 g, 1.18 mmol) and 1.1 equiv of 7chlorocarbonyl-heptanoic acid methyl ester dissolved in dichloromethane (DCM, 3 mL) under N 2 for overnight.…”

“…This dual inhibitor possesses antitumor efficacy in malignancies sensitive/resistant to LSD1 inhibitors, such as cutaneous squamous cell cancer and melanoma respectively. Catalytic amine oxidase domain (AOD) of LSD1 requires Flavin adenine dinucleotide (FAD) as a cofactor thus; all members of the LSD1 family are FAD-dependent oxidation enzymes intriguingly similar to monoamine oxidases A and B (MAOs) . Due to the similar homologies of LSD1 and MAOs, LSD1 may potentially catalyze its oxidation reactions with a mechanism similar to that of MAOs.…”

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

“…[5,6] One approach to targeting LSD1 involves the repurposing of monoamine oxidase (MAO) inhibitors that disrupt the FAD cofactor common to both enzymes. [7,8] The approved antidepressant (�)-tranylcypromine (1, Figure 1) for example, is a substrate mimic that is oxidized to radical cation 2, followed by strain induced cyclopropyl ring opening to the reactive intermediate 3 which covalently modifies FAD. Since the cofactor is tightly bound to LSD1, with one study reporting a K d of 180 nM, [9] the formation of tranylcypromine-FAD adducts effectively results in irreversible enzyme inactivation.…”

Synthesis of Carboxamides Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors for AML

“…[5,6] One approach to targeting LSD1 involves the repurposing of monoamine oxidase (MAO) inhibitors that disrupt the FAD cofactor common to both enzymes. [7,8] The approved antidepressant (±)-tranylcypromine (1, Figure 1) for example, is a substrate mimic that is oxidized to radical cation 2, followed by strain induced cyclopropyl ring opening to the reactive intermediate 3 which covalently modifies FAD. Since the cofactor is tightly bound to LSD1, with one study reporting a Kd of 180 nM, [9] the formation of tranylcypromine-FAD adducts effectively results in irreversible enzyme inactivation.…”

“…formylbenzoate(8): 4-Formylbenzoic acid (10.0 g, 66.0 mol, 1.0 equiv.) was dissolved in anhydrous MeOH (100 mL) with cooling (-5 °C) and acetyl chloride (24.1 g, , 21.2 mL, 0.33 mol, 5.0 equiv.)…”