Top Med Chem (2020) 33: 221–254
DOI: 10.1007/7355_2019_75
© Springer Nature Switzerland AG 2019
Published online: 14 January 2020
Inhibitors of JmjC-Containing Histone
Demethylases
Miranda Wright, Paul E. Brennan, and Akane Kawamura
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
1.1 JmjC-Domain-Containing Histone Demethylases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
1.2 JmjC-KDM Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
2 Mechanism and Structure of JmjC-KDMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2.1 Structural Alignment of JmjC-KDMs . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 226
3 Development of JmjC-KDM Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
3.1 Inhibitors Targeting the 2OG Binding Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
3.2 Substrate Competitive Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Abstract Histone demethylases (KDMs) catalyse the removal of N-methyl marks
on histones and play important roles in epigenetic regulation. Abnormal histone
methylation and dysregulation of KDMs have been linked to multiple diseases, and
KDMs are emerging as promising therapeutic targets. This chapter provides an
overview of JmjC-domain-containing KDMs (JmjC-KDMs), with a particular
focus on recent advances in JmjC-KDM inhibitor development from a structural
perspective.
Keywords 2OG oxygenases, JmjC histone demethylases, KDMs
M. Wright and P. E. Brennan
Structural Genomics Consortium (SGC), University of Oxford, Oxford, UK
Nuffield Department of Medicine, Target Discovery Institute, University of Oxford,
Oxford, UK
A. Kawamura (*)
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK
Radcliffe Department of Medicine, Wellcome Centre for Human Genetics, University of
Oxford, Oxford, UK
e-mail: akane.kawamura@chem.ox.ac.uk
DOI: 10.1007/7355_2019_75
© Springer Nature Switzerland AG 2019
Published online: 14 January 2020
Inhibitors of JmjC-Containing Histone
Demethylases
Miranda Wright, Paul E. Brennan, and Akane Kawamura
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
1.1 JmjC-Domain-Containing Histone Demethylases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
1.2 JmjC-KDM Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
2 Mechanism and Structure of JmjC-KDMs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2.1 Structural Alignment of JmjC-KDMs . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 226
3 Development of JmjC-KDM Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
3.1 Inhibitors Targeting the 2OG Binding Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
3.2 Substrate Competitive Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Abstract Histone demethylases (KDMs) catalyse the removal of N-methyl marks
on histones and play important roles in epigenetic regulation. Abnormal histone
methylation and dysregulation of KDMs have been linked to multiple diseases, and
KDMs are emerging as promising therapeutic targets. This chapter provides an
overview of JmjC-domain-containing KDMs (JmjC-KDMs), with a particular
focus on recent advances in JmjC-KDM inhibitor development from a structural
perspective.
Keywords 2OG oxygenases, JmjC histone demethylases, KDMs
M. Wright and P. E. Brennan
Structural Genomics Consortium (SGC), University of Oxford, Oxford, UK
Nuffield Department of Medicine, Target Discovery Institute, University of Oxford,
Oxford, UK
A. Kawamura (*)
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK
Radcliffe Department of Medicine, Wellcome Centre for Human Genetics, University of
Oxford, Oxford, UK
e-mail: akane.kawamura@chem.ox.ac.uk