LSD1 and LSD2
histone demethylases are implicated in a number of physiological and
pathological processes, ranging from
tumorigenesis to herpes
virus infection. A comprehensive structural, biochemical, and cellular study is presented here to probe the potential of these
enzymes for epigenetic
therapies. This approach employs
tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. This
drug is a clinically validated
antidepressant known to target monoamine
oxidases A and B. These two flavoenzymes are structurally related to LSD1 and LSD2. Mechanistic and crystallographic studies of
tranylcypromine inhibition reveal a lack of selectivity and differing covalent modifications of the
FAD cofactor depending on the enantiomeric form. These findings are pharmacologically relevant, since
tranylcypromine is currently administered as a racemic mixture. A large set of
tranylcypromine analogues were synthesized and screened for inhibitory activities. We found that the common evolutionary origin of
LSD and
MAO enzymes, despite their unrelated functions and substrate specificities, is reflected in related
ligand-binding properties. A few compounds with partial
enzyme selectivity were identified. The
biological activity of one of these new inhibitors was evaluated with a cellular model of
acute promyelocytic leukemia chosen since its pathogenesis includes aberrant activities of several
chromatin modifiers. Marked effects on cell differentiation and an unprecedented synergistic activity with antileukemia drugs were observed. These data demonstrate that these LSD1/2 inhibitors are of potential relevance for the treatment of promyelocytic
leukemia and, more generally, as tools to alter
chromatin state with promise of a block of
tumor progression.