4.5 Link of LSD1 to Central Nervous System (CNS) Disorders
LSD1 has been reported to be involved in central nervous system (CNS) disorders,
such as depression and Alzheimer’s disease. LSD1 regulates the expression of genes
associated with cognitive function, neuroplasticity, and memory in senescenceaccelerated SAMP8 mice [49]. LSD1 also controls the expression of genes related
to immune reaction and inflammation, including S100A9, which is emerging as an
important contributor to inflammation-related neurodegeneration.
It was reported that neuroLSD1, a dominant-negative splicing isoform of LSD1,
is responsible for emotional behavior [50]. The knockout of neuroLSD1 in mutant
mice reduces the expression of psychosocial-stress-induced genes, resulting in low
anxiety-like behavior.
5 LSD1 Inhibitors and Their Biological/Therapeutic
Applications
As mentioned above, LSD1 represents an interesting target for epigenetic drugs as
supported by data related to its link to several diseases, including cancer, viral
infection, globin disorders, metabolic diseases, and CNS disorders. Thus, expectations are high regarding the use of LSD1 inhibitors as therapeutic agents for cancer
and non-cancer diseases. In this section, some of the previously reported LSD1
inhibitors (Fig. 2) and their potential as therapeutic agents are presented.
LSD1 is an amine oxidase that catalyzes the demethylation of mono- or
dimethylated histone lysine residues and shows homology with monoamine oxidases (MAOs) A and B [51]. Indeed, trans-2-phenylcyclopropylamine (PCPA)
(Fig. 2), a MAO inhibitor used as an antidepressant, was found to be also able to
inhibit LSD1 and LSD2 [13, 51]. It was shown that PCPA is a mechanism-based
irreversible inhibitor of LSD1. Kinetics, MS, and X-ray analysis data suggested
that PCPA inhibits LSD1 through the formation of a covalent adduct with the flavin
ring following one-electron oxidation and cyclopropyl ring opening (Fig. 3)
[51, 52]. PCPA at high concentrations induces an increase of global H3K4 methylation and growth inhibition of neuroblastoma cells and bladder cancer cells
[25, 53]. In addition, the combination of PCPA and all-trans-retinoic acid (ATRA)
is an effective therapy for acute myelogenous leukemia (AML) [54]. In addition to
cancer, PCPA has been reported to show pharmacological effects in α-herpes virus
latent infection [41], globin disorders [47], metabolic disorders [48], and neurodegenerative disorders [55], suggesting that LSD1 inhibitors are useful as therapeutic
agents for not only cancer but also non-cancerous diseases.
Ueda et al. designed LSD1-selective inhibitors on the basis of the structures of the
methylated lysine substrate and PCPA (Fig. 4) [56]. PCPA-lysine analog hybrid
compounds are expected to be potent LSD1-selective inhibitors because they can
Lysine-Specific Histone Demethylases 1/2 (LSD1/2) and Their Inhibitors
203
LSD1 has been reported to be involved in central nervous system (CNS) disorders,
such as depression and Alzheimer’s disease. LSD1 regulates the expression of genes
associated with cognitive function, neuroplasticity, and memory in senescenceaccelerated SAMP8 mice [49]. LSD1 also controls the expression of genes related
to immune reaction and inflammation, including S100A9, which is emerging as an
important contributor to inflammation-related neurodegeneration.
It was reported that neuroLSD1, a dominant-negative splicing isoform of LSD1,
is responsible for emotional behavior [50]. The knockout of neuroLSD1 in mutant
mice reduces the expression of psychosocial-stress-induced genes, resulting in low
anxiety-like behavior.
5 LSD1 Inhibitors and Their Biological/Therapeutic
Applications
As mentioned above, LSD1 represents an interesting target for epigenetic drugs as
supported by data related to its link to several diseases, including cancer, viral
infection, globin disorders, metabolic diseases, and CNS disorders. Thus, expectations are high regarding the use of LSD1 inhibitors as therapeutic agents for cancer
and non-cancer diseases. In this section, some of the previously reported LSD1
inhibitors (Fig. 2) and their potential as therapeutic agents are presented.
LSD1 is an amine oxidase that catalyzes the demethylation of mono- or
dimethylated histone lysine residues and shows homology with monoamine oxidases (MAOs) A and B [51]. Indeed, trans-2-phenylcyclopropylamine (PCPA)
(Fig. 2), a MAO inhibitor used as an antidepressant, was found to be also able to
inhibit LSD1 and LSD2 [13, 51]. It was shown that PCPA is a mechanism-based
irreversible inhibitor of LSD1. Kinetics, MS, and X-ray analysis data suggested
that PCPA inhibits LSD1 through the formation of a covalent adduct with the flavin
ring following one-electron oxidation and cyclopropyl ring opening (Fig. 3)
[51, 52]. PCPA at high concentrations induces an increase of global H3K4 methylation and growth inhibition of neuroblastoma cells and bladder cancer cells
[25, 53]. In addition, the combination of PCPA and all-trans-retinoic acid (ATRA)
is an effective therapy for acute myelogenous leukemia (AML) [54]. In addition to
cancer, PCPA has been reported to show pharmacological effects in α-herpes virus
latent infection [41], globin disorders [47], metabolic disorders [48], and neurodegenerative disorders [55], suggesting that LSD1 inhibitors are useful as therapeutic
agents for not only cancer but also non-cancerous diseases.
Ueda et al. designed LSD1-selective inhibitors on the basis of the structures of the
methylated lysine substrate and PCPA (Fig. 4) [56]. PCPA-lysine analog hybrid
compounds are expected to be potent LSD1-selective inhibitors because they can
Lysine-Specific Histone Demethylases 1/2 (LSD1/2) and Their Inhibitors
203