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An Activity-Based Probe Targeting Non-Catalytic, Highly Conserved Amino Acid Residues within Bromodomains.

Melissa D'AscenzioKathryn M PughRebecca KonietznyGeorgina BerridgeCynthia TallantShaima HashemOctovia MonteiroJason R ThomasMarkus SchirleStefan KnappBrian MarsdenOleg FedorovChas BountraBenedikt M KesslerPaul E Brennan
Published in: Angewandte Chemie (International ed. in English) (2018)
Bromodomain-containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl-lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule-based approach to covalently modify recombinant and endogenous bromodomain-containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in-gel visualization and pull-down of the desired bromodomains.
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