Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology. (September 2016)

• Record Type: Journal Article
• Authors: Galdeano, Carles; Ciulli, Alessio
• Is Part Of: Future medicinal chemistry. Volume 8:Number 13(2016)
• Page Start: 1655
• Page End: 1680
• Publication Date: 2016-09
• Subjects: BET bromodomains -- chemical genetics -- chemical probes -- selectivity -- structure-based drug discovery; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.4155/fmc-2016-0059
• Languages: English
• ISSNs: 1756-8919

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.