with anionic amino acid residues of LSD1 [84]. These scaffolds should be useful for
further studies on LSD1 inhibitor development.
6 Summary
At present, there are only six approved epigenetic drugs (two DNMT inhibitors and
four HDAC inhibitors), and they are utilized only for MDS, cutaneous T-cell
lymphoma, peripheral T-cell lymphoma, or multiple myeloma treatment. Additional
indications of the current epigenetic drugs are limited. In this regard, researchers
need to acquire an integrated understanding of cancer epigenetics in order to
discover useful next-generation drugs for cancer therapy.
In this chapter, the biology and pharmacology of LSD and hitherto reported LSD
inhibitors have been presented. In particular, small-molecule LSD1 inhibitors have
been discussed from the point of view of potential therapeutic agents. It is hoped that
the LSD1-selective inhibitors presented here will provide the basis for the development of novel therapeutic agents for both cancer and non-cancerous diseases.
Compliance with Ethical Standards
Funding: This work was partially supported by the JST CREST program (T.S.; JPMJCR14L2).
Conflict of Interest: The author declares no conflict of interest.
Ethical Approval: Not applicable.
Informed Consent: Not applicable.
References
1. Kubicek S, Jenuwein T (2004) A crack in histone lysine methylation. Cell 119:903–906
2. Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436:1103–1106
3. Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC, Schreiber SL,
Mellor J, Kouzarides T (2002) Active genes are tri-methylated at K4 of histone H3. Nature
419:407–411
4. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K
(2007) High-resolution profiling of histone methylations in the human genome. Cell
129:823–837
5. Itoh Y, Suzuki T, Miyata N (2013) Small-molecular modulators of cancer-associated epigenetic
mechanisms. Mol Biosyst 9:873–896
6. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone
demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953
7. Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AH, Günther T, Buettner R,
Schüle R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptordependent transcription. Nature 437:436–439
8. Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R,
Bedford MT, Jenuwein T, Berger SL (2007) p53 is regulated by the lysine demethylase LSD1.
Nature 449:105–108
214
T. Suzuki
further studies on LSD1 inhibitor development.
6 Summary
At present, there are only six approved epigenetic drugs (two DNMT inhibitors and
four HDAC inhibitors), and they are utilized only for MDS, cutaneous T-cell
lymphoma, peripheral T-cell lymphoma, or multiple myeloma treatment. Additional
indications of the current epigenetic drugs are limited. In this regard, researchers
need to acquire an integrated understanding of cancer epigenetics in order to
discover useful next-generation drugs for cancer therapy.
In this chapter, the biology and pharmacology of LSD and hitherto reported LSD
inhibitors have been presented. In particular, small-molecule LSD1 inhibitors have
been discussed from the point of view of potential therapeutic agents. It is hoped that
the LSD1-selective inhibitors presented here will provide the basis for the development of novel therapeutic agents for both cancer and non-cancerous diseases.
Compliance with Ethical Standards
Funding: This work was partially supported by the JST CREST program (T.S.; JPMJCR14L2).
Conflict of Interest: The author declares no conflict of interest.
Ethical Approval: Not applicable.
Informed Consent: Not applicable.
References
1. Kubicek S, Jenuwein T (2004) A crack in histone lysine methylation. Cell 119:903–906
2. Bannister AJ, Kouzarides T (2005) Reversing histone methylation. Nature 436:1103–1106
3. Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC, Schreiber SL,
Mellor J, Kouzarides T (2002) Active genes are tri-methylated at K4 of histone H3. Nature
419:407–411
4. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K
(2007) High-resolution profiling of histone methylations in the human genome. Cell
129:823–837
5. Itoh Y, Suzuki T, Miyata N (2013) Small-molecular modulators of cancer-associated epigenetic
mechanisms. Mol Biosyst 9:873–896
6. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y (2004) Histone
demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119:941–953
7. Metzger E, Wissmann M, Yin N, Müller JM, Schneider R, Peters AH, Günther T, Buettner R,
Schüle R (2005) LSD1 demethylates repressive histone marks to promote androgen-receptordependent transcription. Nature 437:436–439
8. Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R,
Bedford MT, Jenuwein T, Berger SL (2007) p53 is regulated by the lysine demethylase LSD1.
Nature 449:105–108
214
T. Suzuki