Top Med Chem (2020) 33: 93–122
DOI: 10.1007/7355_2019_71
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Histone Acetyltransferase Enzymes: From
Biological Implications to Most Relevant
Inhibitors
Daniela Trisciuoglio and Dante Rotili
Contents
1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2 HAT Superfamilies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3 HAT and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4 HAT and Other Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
5 HAT Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6 Bisubstrate Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
7 Natural Products and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
8 Synthetic Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
9 Conclusions and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Abstract The acetylation of lysine residues of histone and nonhistone proteins is a
post-translational modification catalysed by the so-called histone acetyltransferases
(HATs) that plays a crucial role in several biological settings. The deregulation of
this enzymatic activity is implicated in many disease conditions such as cancer and
inflammatory and neurological disorders. Despite many histone acetyltransferase
inhibitors (HATi) have been identified so far, there is still the need for new,
metabolically stable, more potent and selective HATi as potential therapeutic agents
and/or as chemical tools for studying HAT biology. In the present chapter, the main
features of HAT enzymes and related diseases have been summarized, with a
particular focus on HATi, analysing their structure-activity relationships, mechanisms of action and potential therapeutic applications.
D. Trisciuoglio (*)
Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer
Institute, Rome, Italy
e-mail: daniela.trisciuoglio@uniroma1.it
D. Rotili (*)
Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, Rome,
Italy
e-mail: dante.rotili@uniroma1.it
DOI: 10.1007/7355_2019_71
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Histone Acetyltransferase Enzymes: From
Biological Implications to Most Relevant
Inhibitors
Daniela Trisciuoglio and Dante Rotili
Contents
1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2 HAT Superfamilies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
3 HAT and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
4 HAT and Other Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
5 HAT Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
6 Bisubstrate Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
7 Natural Products and Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
8 Synthetic Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
9 Conclusions and Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Abstract The acetylation of lysine residues of histone and nonhistone proteins is a
post-translational modification catalysed by the so-called histone acetyltransferases
(HATs) that plays a crucial role in several biological settings. The deregulation of
this enzymatic activity is implicated in many disease conditions such as cancer and
inflammatory and neurological disorders. Despite many histone acetyltransferase
inhibitors (HATi) have been identified so far, there is still the need for new,
metabolically stable, more potent and selective HATi as potential therapeutic agents
and/or as chemical tools for studying HAT biology. In the present chapter, the main
features of HAT enzymes and related diseases have been summarized, with a
particular focus on HATi, analysing their structure-activity relationships, mechanisms of action and potential therapeutic applications.
D. Trisciuoglio (*)
Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer
Institute, Rome, Italy
e-mail: daniela.trisciuoglio@uniroma1.it
D. Rotili (*)
Department of Chemistry and Technologies of Drugs, Sapienza University of Rome, Rome,
Italy
e-mail: dante.rotili@uniroma1.it