Top Med Chem (2020) 33: 287–338
DOI: 10.1007/7355_2019_79
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Applied Biophysics for Bromodomain Drug
Discovery
William C. K. Pomerantz, Jorden A. Johnson, and Peter D. Ycas
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
2 Part I: Timeline of Bromodomain Discovery and Characterization . . . . . . . . . . . . . . . . . . . . . . . . 290
2.1 Discovery of the Bromodomain Structural Motif . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
2.2 Structural Biology Studies of Bromodomains Pave the Way for Drug Discovery
Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
3 Part II: Early Small-Molecule Bromodomain Inhibitor Discovery . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.1 PCAF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2 CBP/p300 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
3.3 BETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
3.4 Bromodomain Clinical Trials and Chemical Probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
4 Part III: Computational and Experimental Biophysical Methods for Bromodomain
Inhibitor Development . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . 306
4.1 High-Throughput Virtual Screens and Molecular Dynamic Simulations
for Bromodomain Inhibitor Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
4.2 Direct-Binding Experiments with Bromodomains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
4.3 Competition-Based Assays for Inhibitor Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
4.4 Crystallography Guides Rational Design of Bromodomain Inhibitors . . . . . . . . . . . . . . 322
5 Future Outlook on Bromodomain Inhibitor Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Abstract The dynamic regulation of epigenetic processes is dictated by the addition, removal, and recognition of posttranslational modifications on proteins and
nucleic acids. These processes further regulate how our genetic information is
accessed within chromatin. The recognition of acetylated histones by bromodomain
modules is one such process that has been significantly evaluated as a promising
interaction to disrupt for developing epigenetic therapies. The discovery of such
inhibitors has been aided by the application of a wealth of biophysical and computational tools leading to insights into the structural biology of bromodomains and
potent inhibitors that are advancing in the clinic. This chapter will first provide a
W. C. K. Pomerantz (*), J. A. Johnson, and P. D. Ycas
Department of Chemistry, University of Minnesota, Minneapolis, MN, USA
e-mail: wcp@umn.edu
DOI: 10.1007/7355_2019_79
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Applied Biophysics for Bromodomain Drug
Discovery
William C. K. Pomerantz, Jorden A. Johnson, and Peter D. Ycas
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
2 Part I: Timeline of Bromodomain Discovery and Characterization . . . . . . . . . . . . . . . . . . . . . . . . 290
2.1 Discovery of the Bromodomain Structural Motif . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
2.2 Structural Biology Studies of Bromodomains Pave the Way for Drug Discovery
Efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
3 Part II: Early Small-Molecule Bromodomain Inhibitor Discovery . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.1 PCAF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
3.2 CBP/p300 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
3.3 BETs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
3.4 Bromodomain Clinical Trials and Chemical Probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
4 Part III: Computational and Experimental Biophysical Methods for Bromodomain
Inhibitor Development . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . 306
4.1 High-Throughput Virtual Screens and Molecular Dynamic Simulations
for Bromodomain Inhibitor Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
4.2 Direct-Binding Experiments with Bromodomains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308
4.3 Competition-Based Assays for Inhibitor Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
4.4 Crystallography Guides Rational Design of Bromodomain Inhibitors . . . . . . . . . . . . . . 322
5 Future Outlook on Bromodomain Inhibitor Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Abstract The dynamic regulation of epigenetic processes is dictated by the addition, removal, and recognition of posttranslational modifications on proteins and
nucleic acids. These processes further regulate how our genetic information is
accessed within chromatin. The recognition of acetylated histones by bromodomain
modules is one such process that has been significantly evaluated as a promising
interaction to disrupt for developing epigenetic therapies. The discovery of such
inhibitors has been aided by the application of a wealth of biophysical and computational tools leading to insights into the structural biology of bromodomains and
potent inhibitors that are advancing in the clinic. This chapter will first provide a
W. C. K. Pomerantz (*), J. A. Johnson, and P. D. Ycas
Department of Chemistry, University of Minnesota, Minneapolis, MN, USA
e-mail: wcp@umn.edu