Journal
FUTURE MEDICINAL CHEMISTRY
Volume 8, Issue 13, Pages 1655-1680Publisher
FUTURE SCI LTD
DOI: 10.4155/fmc-2016-0059
Keywords
BET bromodomains; chemical genetics; chemical probes; selectivity; structure-based drug discovery
Categories
Funding
- European Research Council [ERC-2012-StG-311460 DrugE3CRLs]
- UK Biotechnology and Biological Sciences Research Council (BBSRC) [BB/J001201/2, BB/G023123/2]
- European Commission [PIEF-GA-2012-328030]
- European Framework Program-Marie Curie COFUND [600385]
- Wellcome Trust [100476/Z/12/Z]
- BBSRC [BB/G023123/2, BB/J001201/2] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/G023123/2, BB/J001201/2] Funding Source: researchfish
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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.
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