Top Med Chem (2020) 33: 123–158
DOI: 10.1007/7355_2019_72
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Lysine Methyltransferases and Their
Inhibitors
Giulia Stazi, Clemens Zwergel, and Sergio Valente
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
1.1
The H3K9 Methyltransferases EHMT1 and EHMT2 (GLP and G9a) . . . . . . . . . . . . . 126
1.2
The H3K9 Methyltransferase SETDB1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
1.3
The H3K9 Methyltransferases SUV39H1 and SUV39H2 . . . . . . . . . . . . . . . . . . . . . . . . . . 130
1.4
The H3K27 Methyltransferases EZH1 and EZH2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
1.5
The H3K79 Histone Methyltransferase DOT1L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
1.6
The H3K4 Histone Methyltransferases SET1/MLL Family: MLL1–4 and SETD1A
and 1B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
1.7
The H3K4 Histone Methyltransferase SETD7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
1.8
The H3K4 Histone Methyltransferase SMYD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
1.9
The H3K36 Histone Methyltransferase SETD2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.10 The H4K20 Histone Methyltransferases SETD8, SUV420H1, and SUV420H2 . . 144
2 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Abstract Since 2000, the histone methyltransferases that catalyze the methylation
of a number of histone and nonhistone substrates have been discovered.
A growing body of literature is indicating that lysine methyltransferases (KMTs)
play a crucial role for transcriptional regulation and are involved in cancer and
various other human diseases, thus being of high interest as potential therapeutic
targets.
In this book chapter, we highlight the discovery, characterization, and application
of selective KMT inhibitors, useful for dissecting their physiological functions as
well as their disease implications.
Over the past decade, there has been an impressive progress regarding the KMT
inhibitor discovery, especially conjugating the research interest with the available
and novel techniques including new assay methods, high-throughput screening,
G. Stazi, C. Zwergel, and S. Valente (*)
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
e-mail: sergio.valente@uniroma1.it
DOI: 10.1007/7355_2019_72
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Lysine Methyltransferases and Their
Inhibitors
Giulia Stazi, Clemens Zwergel, and Sergio Valente
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
1.1
The H3K9 Methyltransferases EHMT1 and EHMT2 (GLP and G9a) . . . . . . . . . . . . . 126
1.2
The H3K9 Methyltransferase SETDB1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
1.3
The H3K9 Methyltransferases SUV39H1 and SUV39H2 . . . . . . . . . . . . . . . . . . . . . . . . . . 130
1.4
The H3K27 Methyltransferases EZH1 and EZH2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
1.5
The H3K79 Histone Methyltransferase DOT1L . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
1.6
The H3K4 Histone Methyltransferases SET1/MLL Family: MLL1–4 and SETD1A
and 1B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
1.7
The H3K4 Histone Methyltransferase SETD7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
1.8
The H3K4 Histone Methyltransferase SMYD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
1.9
The H3K36 Histone Methyltransferase SETD2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
1.10 The H4K20 Histone Methyltransferases SETD8, SUV420H1, and SUV420H2 . . 144
2 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Abstract Since 2000, the histone methyltransferases that catalyze the methylation
of a number of histone and nonhistone substrates have been discovered.
A growing body of literature is indicating that lysine methyltransferases (KMTs)
play a crucial role for transcriptional regulation and are involved in cancer and
various other human diseases, thus being of high interest as potential therapeutic
targets.
In this book chapter, we highlight the discovery, characterization, and application
of selective KMT inhibitors, useful for dissecting their physiological functions as
well as their disease implications.
Over the past decade, there has been an impressive progress regarding the KMT
inhibitor discovery, especially conjugating the research interest with the available
and novel techniques including new assay methods, high-throughput screening,
G. Stazi, C. Zwergel, and S. Valente (*)
Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy
e-mail: sergio.valente@uniroma1.it