Top Med Chem (2020) 33: 197–220
DOI: 10.1007/7355_2019_74
© Springer Nature Switzerland AG 2019
Published online: 15 January 2020
Lysine-Specific Histone Demethylases 1/2
(LSD1/2) and Their Inhibitors
Takayoshi Suzuki
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2 Biology of Lysine-Specific Histone Demethylases 1/2 (LSD1/2) . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3 Structural Studies and Catalytic Mechanism of LSD1/2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
4 Link of LSD1/2 to Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
4.1 Link of LSD1/2 to Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.2 Link of LSD1 to Viral Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.3 Link of LSD1 to Globin Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.4 Link of LSD1 to Metabolic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.5 Link of LSD1 to Central Nervous System (CNS) Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 203
5 LSD1 Inhibitors and Their Biological/Therapeutic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . 203
6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Abstract Histone lysine methylation, one of the epigenetic mechanisms, plays a
pivotal role in various biological events, including cell cycle progression, immune
response, and signal transduction. Histone methylation is closely associated with the
oncogenesis and proliferation of cancer cells, and its alteration has been identified in
many cancer cells. In addition, histone methylation is involved in such non-cancerous
diseases as globin disorders and neurological disorders. Several enzymes that control
histone methylation have been identified, including lysine-specific histone
demethylases 1/2 (LSD1/2). As LSD1/2 are involved in various diseases, their
inhibitors are considered useful not only as a chemical tool for probing the biology
of LSD1/2 but also as therapeutic agents. In this chapter, the biology, pharmacology,
and inhibitors of LSD1/2 are presented, and the potential of LSD inhibitors as
therapeutic agents is discussed.
T. Suzuki (*)
The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan
e-mail: tkyssuzuki@sanken.osaka-u.ac.jp
DOI: 10.1007/7355_2019_74
© Springer Nature Switzerland AG 2019
Published online: 15 January 2020
Lysine-Specific Histone Demethylases 1/2
(LSD1/2) and Their Inhibitors
Takayoshi Suzuki
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2 Biology of Lysine-Specific Histone Demethylases 1/2 (LSD1/2) . . . . . . . . . . . . . . . . . . . . . . . . . . 199
3 Structural Studies and Catalytic Mechanism of LSD1/2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
4 Link of LSD1/2 to Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
4.1 Link of LSD1/2 to Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.2 Link of LSD1 to Viral Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
4.3 Link of LSD1 to Globin Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.4 Link of LSD1 to Metabolic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4.5 Link of LSD1 to Central Nervous System (CNS) Disorders . . . . . . . . . . . . . . . . . . . . . . . . . 203
5 LSD1 Inhibitors and Their Biological/Therapeutic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . 203
6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Abstract Histone lysine methylation, one of the epigenetic mechanisms, plays a
pivotal role in various biological events, including cell cycle progression, immune
response, and signal transduction. Histone methylation is closely associated with the
oncogenesis and proliferation of cancer cells, and its alteration has been identified in
many cancer cells. In addition, histone methylation is involved in such non-cancerous
diseases as globin disorders and neurological disorders. Several enzymes that control
histone methylation have been identified, including lysine-specific histone
demethylases 1/2 (LSD1/2). As LSD1/2 are involved in various diseases, their
inhibitors are considered useful not only as a chemical tool for probing the biology
of LSD1/2 but also as therapeutic agents. In this chapter, the biology, pharmacology,
and inhibitors of LSD1/2 are presented, and the potential of LSD inhibitors as
therapeutic agents is discussed.
T. Suzuki (*)
The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan
e-mail: tkyssuzuki@sanken.osaka-u.ac.jp