Bromodomain biology and drug discovery

Abstract

The bromodomain (BrD) is a conserved structural module found in chromatin- and transcription-associated proteins that acts as the primary reader for acetylated lysine residues. This basic activity endows BrD proteins with versatile functions in the regulation of protein-protein interactions mediating chromatin-templated gene transcription, DNA recombination, replication and repair. Consequently, BrD proteins are involved in the pathogenesis of numerous human diseases. In this Review, we highlight our current understanding of BrD biology, and discuss the latest development of small-molecule inhibitors targeting BrDs as emerging epigenetic therapies for cancer and inflammatory disorders.

Fig. 1 ∣. Three-dimensional structure and Kac binding mode of the bromodomain.

a, NMR spectroscopy structure of the PCAF BrD (PDB 1N72), depicted in a ribbon representation. The four helices (αZ, αA, αB, αC) of the left-handed bundle BrD fold and the two inter-helical connecting ZA and BC loops are labeled. The conserved asparagine residue, Asn803, is highlighted in yellow. b, Superimposition of the two-dimensional ¹⁵N-HSQC spectra of the PCAF BrD in the free form (red) and in complex with an acetylated histone H4 peptide (black). Image adapted from ref. . Reprinted by permission from Nature. c, Ribbon diagram of the crystal structure of a H4K5ac/K8ac peptide bound to BRD4-BD1 (PDB 3UVW). Side chains of key protein residues involved in ligand recognition are labeled. d, Crystal structure of JQ1 bound to BRD4-BD1 (PDB 3MXF). Side chains of key protein residues involved in ligand recognition are labeled. The bound water molecules at the base of the Kac binding pocket are shown as red spheres.

Fig. 2 ∣. Classification of BrD-containing proteins based on major known functions.

Key functional domains in each protein are highlighted, with the BrD in purple.

Fig. 3 ∣. 3D structures of representative BrDs in different forms.

a, Crystal structure of the BrD-PHD-HAT module of human p300 (PDB 4BHW). The BrD-PHD module is rendered in green and yellow, RING domain in blue and HAT domain in cyan. Lys-CoA is displayed as a stick model. b, Crystal structure of double BrDs of TAF_∥250 (PDB 1EQF). c, Left, crystal structure of the BPTF PHD-BrD (PDB 3QZV), with α-helix connecting the two domains (red). Middle, crystal structure of the TRIM33 PHD-BrD module in complex with the H3K9me3/K18ac peptide (magenta) (PDB 3U5P). Right, the solution structure of the PHD-BrD module of TRIM28 (PDB 2RO1). Three of the four BrD helices are depicted in green; the fourth, αZ, colored in red, is highlighted because it serves as the hydrophobic center of the tandem structure. d, Crystal structure of bivalent BET BrD inhibitor MS645 bound to the BRD4 BD1 dimer (PDB 6DJC), displayed in ribbon and spacefilled surface depictions. MS645 (yellow) is color-coded by atom type.

Fig. 4 ∣. Representative small-molecule inhibitors and PROTACs for selected BrDs.

Chemical structures of representative BrD inhibitors are shown. Additional examples are in Supplementary Table 2. Properties and cellular effects are discussed in main text.

Fig. 5 ∣. Illustrative diagram highlighting representative functions of nine subclasses of human BrD proteins.

Center, stick diagram depicting atomic details of molecular recognition of the acetyl-lysine of the H4K16ac peptide by the BrD of GCN5L2 (PDB 1E6I). Side chains of key protein residues involved in Kac binding are color-coded by atom type. Conserved water molecules in the Kac binding pocket are in red.