Phenotypic screening and fragment-based approaches to the discovery of small-molecule bromodomain ligands.
Bromodomains are protein modules that bind to acetylated lysine residues and hence facilitate protein-protein interactions. These bromodomain-mediated interactions often play key roles in transcriptional regulation and their dysfunction is implicated in a large number of diseases. The discovery of potent and selective small-molecule bromodomain and extra C-terminal domain bromodomain ligands, which show promising results for the treatment of cancers and atherosclerosis, has promoted intense interest in this area. Here we describe the progress that has been made to date in the discovery of small-molecule bromodomain ligands, with particular emphasis on the roles played by phenotypic screening and fragment-based approaches. In considering the future of the field we discuss the prospects for development of molecular probes and drugs for the non-bromodomain and extra C-terminal domain bromodomains.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
Laura E
LE
Jennings
Angelina R
AR
Measures
Brian G
BG
Wilson
Stuart J
SJ
Conway
D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism*
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D008024:Ligands; D054852:Small Molecule Libraries; D017346:Protein Serine-Threonine Kinases