title: Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology.
abstract: Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity.
authors.affiliation: Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.|Institut de Biomedicina de la Universitat de Barcelona (IBUB) & Departament de Fisicoquímica, Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Galdeano
authors.affiliation: Division of Biological Chemistry & Drug Discovery, School of Life Sciences, University of Dundee, James Black Centre, Dow Street, Dundee, DD1 5EH, UK.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D002626:Chemistry, Pharmaceutical; D008958:Models, Molecular; D015394:Molecular Structure; D000072417:Protein Domains / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries
keywords: BET bromodomains; chemical genetics; chemical probes; selectivity; structure-based drug discovery