title: Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes.
abstract: Small molecules are useful tools for probing the biological function and therapeutic potential of individual proteins, but achieving selectivity is challenging when the target protein shares structural domains with other proteins. The Bromo and Extra-Terminal (BET) proteins have attracted interest because of their roles in transcriptional regulation, epigenetics, and cancer. The BET bromodomains (protein interaction modules that bind acetyl-lysine) have been targeted by potent small-molecule inhibitors, but these inhibitors lack selectivity for individual family members. We developed an ethyl derivative of an existing small-molecule inhibitor, I-BET/JQ1, and showed that it binds leucine/alanine mutant bromodomains with nanomolar affinity and achieves up to 540-fold selectivity relative to wild-type bromodomains. Cell culture studies showed that blockade of the first bromodomain alone is sufficient to displace a specific BET protein, Brd4, from chromatin. Expansion of this approach could help identify the individual roles of single BET proteins in human physiology and disease.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.|Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Matthias G J
authors.initials: MGJ
authors.lastname: Baud
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.|Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Enrique
authors.initials: E
authors.lastname: Lin-Shiao
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Cardote
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Annica
authors.initials: A
authors.lastname: Pschibul
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Kwok-Ho
authors.initials: KH
authors.lastname: Chan
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Zengerle
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Jordi R
authors.initials: JR
authors.lastname: Garcia
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Terence T-L
authors.initials: TT
authors.lastname: Kwan
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Fleur M
authors.initials: FM
authors.lastname: Ferguson
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.|Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D000595:Amino Acid Sequence; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D007930:Leucine / Q000235:genetics; D008958:Models, Molecular; D015335:Molecular Probes / Q000737:chemistry*; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D015202:Protein Engineering / Q000379:methods*; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D002843:Chromatin; D007930:Leucine; D015335:Molecular Probes; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins