Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology

Carles Galdeano, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journalArticle

37 Citations (Scopus)
590 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1655-1680
Number of pages26
JournalFuture Medicinal Chemistry
Volume8
Issue number13
Early online date19 May 2016
DOIs
Publication statusPublished - Sep 2016

Keywords

  • BET bromodomains
  • chemical genetics
  • chemical probes
  • selectivity
  • structure-based drug discovery

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