A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes

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Science  31 Oct 2014:
Vol. 346, Issue 6209, pp. 638-641
DOI: 10.1126/science.1249830

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Epigenetics: It's all about the individual

The bromodomain and extraterminal domain (BET) proteins are a family of epigenetic regulators that affect transcription through interactions with acetylated chromatin. These proteins have attracted interest as drug targets because of their roles in human diseases, including cancer. Parsing out the biological functions of individual family members is important for drug development but has been challenging because of the proteins' shared structural domains. In a proof-of-concept study, Baud et al. used a chemical genetics strategy to design a highly selective small-molecule probe that inhibits the chromatin binding activity of one family member. Extension of this approach may help elucidate the function of individual BET proteins and prioritize them as drug targets.

Science, this issue p. 638


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.

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