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Angew Chem Int Ed Engl. 2019 Jan 21;58(4):1007-1012. doi: 10.1002/anie.201807825. Epub 2018 Dec 27.

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

Author information

1
Structural Genomic Consortium (SGC), University of Oxford, Oxford, OX3 7DQ, UK.
2
Target Discovery Institute (TDI), University of Oxford, Oxford, OX3 7FZ, UK.
3
Novartis Institute for BioMedical Research (NIBR), 180 Massachusetts Ave, Cambridge, MA, 02139, USA.
4
Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University, 60438, Frankfurt am Main, Germany.

Abstract

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.

KEYWORDS:

activity-based protein profiling; bromodomain; chemical proteomics; covalent probes; epigenetics

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