Despite drug discovery efforts targeting bromodomains beginning in earnest only
in the last 8 years, there has been a sharp rise in the literature associated with
chemical epigenetic approaches to study these proteins and manipulate their function
as well as several comprehensive reviews [6, 11–15]. To provide a better understanding for researchers interested in drug discovery and chemical probe development for bromodomains, this book chapter has been broken up into three parts. Part I
gives a brief timeline on the discovery of bromodomains and the structural biology
efforts to characterize human bromodomains. In Part II, we will describe several
early inhibitors of bromodomains which have led to the current clinical candidate
drugs and chemical probes for bromodomains. Finally, in Part III, we provide brief
descriptions of various biophysical and biochemical tools that have been developed
to study these proteins alongside case studies demonstrating how some of these
methods have led to successful inhibitor development. The chapter will close with a
brief outlook on the future of chemical epigenetic approaches for bromodomains.
2 Part I: Timeline of Bromodomain Discovery
and Characterization
2.1 Discovery of the Bromodomain Structural Motif
Although early drug discovery efforts targeting bromodomains did not start until
2005 [16], the first seminal studies of a bromodomain-containing gene were carried
out 13 years earlier by Tamkun et al. in 1992 when they identified the brahma gene
(brm) in Drosophila melanogaster (Fig. 1) [17]. These studies were based on a
genetic screen for activators of gene expression. The brm gene was shown to remove
the suppression of polycomb gene products and activation of src and antp genes
during embryonic development. Brm encodes for a 1638 residue protein, which the
authors found to be homologous to the SNF2/SWI2 protein found in yeast, a protein
that was associated with DNA binding. Within this large protein, a small structural
motif was identified not only in Brm and SNF2 but also in three other proteins fsh,
SPT7, and CCG1, demonstrating the conservation of this structural domain from
flies to yeast and humans. The motif was coined a bromodomain based on similarity
in name to the brahma gene. Prior to bromodomains, the chromatin-associated
chromodomains, which recognize methylated histones, had been identified. It was
later pointed out by Owen et al. that the similarity in nomenclature between
chromodomains and bromodomains also played a role in coining this new protein
domain name [18].
The prediction of the structure and functional roles of the bromodomains began to
slowly emerge after the initial discovery. Based on the original structural prediction
algorithms, bromodomains were thought to be approximately 77 residues, consisting
of 2 helices, αA and αB [19]. The amphipathic character of the helices led
researchers to speculate on their role in protein-protein interactions. Seven conserved
290
W. C. K. Pomerantz et al.
in the last 8 years, there has been a sharp rise in the literature associated with
chemical epigenetic approaches to study these proteins and manipulate their function
as well as several comprehensive reviews [6, 11–15]. To provide a better understanding for researchers interested in drug discovery and chemical probe development for bromodomains, this book chapter has been broken up into three parts. Part I
gives a brief timeline on the discovery of bromodomains and the structural biology
efforts to characterize human bromodomains. In Part II, we will describe several
early inhibitors of bromodomains which have led to the current clinical candidate
drugs and chemical probes for bromodomains. Finally, in Part III, we provide brief
descriptions of various biophysical and biochemical tools that have been developed
to study these proteins alongside case studies demonstrating how some of these
methods have led to successful inhibitor development. The chapter will close with a
brief outlook on the future of chemical epigenetic approaches for bromodomains.
2 Part I: Timeline of Bromodomain Discovery
and Characterization
2.1 Discovery of the Bromodomain Structural Motif
Although early drug discovery efforts targeting bromodomains did not start until
2005 [16], the first seminal studies of a bromodomain-containing gene were carried
out 13 years earlier by Tamkun et al. in 1992 when they identified the brahma gene
(brm) in Drosophila melanogaster (Fig. 1) [17]. These studies were based on a
genetic screen for activators of gene expression. The brm gene was shown to remove
the suppression of polycomb gene products and activation of src and antp genes
during embryonic development. Brm encodes for a 1638 residue protein, which the
authors found to be homologous to the SNF2/SWI2 protein found in yeast, a protein
that was associated with DNA binding. Within this large protein, a small structural
motif was identified not only in Brm and SNF2 but also in three other proteins fsh,
SPT7, and CCG1, demonstrating the conservation of this structural domain from
flies to yeast and humans. The motif was coined a bromodomain based on similarity
in name to the brahma gene. Prior to bromodomains, the chromatin-associated
chromodomains, which recognize methylated histones, had been identified. It was
later pointed out by Owen et al. that the similarity in nomenclature between
chromodomains and bromodomains also played a role in coining this new protein
domain name [18].
The prediction of the structure and functional roles of the bromodomains began to
slowly emerge after the initial discovery. Based on the original structural prediction
algorithms, bromodomains were thought to be approximately 77 residues, consisting
of 2 helices, αA and αB [19]. The amphipathic character of the helices led
researchers to speculate on their role in protein-protein interactions. Seven conserved
290
W. C. K. Pomerantz et al.