 |
PDBsum entry 2xaj
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
2xaj
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Biochemical, Structural, And biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases lsd1 and lsd2.
|
|
|
Authors
|
|
C.Binda,
S.Valente,
M.Romanenghi,
S.Pilotto,
R.Cirilli,
A.Karytinos,
G.Ciossani,
O.A.Botrugno,
F.Forneris,
M.Tardugno,
D.E.Edmondson,
S.Minucci,
A.Mattevi,
A.Mai.
|
|
|
Ref.
|
|
J Am Chem Soc, 2010,
132,
6827-6833.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|
|
|
|
