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An Activity-based Probe Targeting Non-catalytic, Highly Conserved Amino Acid Residues Within Bromodomains

submitted on 16.10.2018, 14:51 and posted on 17.10.2018, 14:16 by Melissa D’Ascenzio, Kathryn Pugh, Rebecca Konietzny, Georgina Berridge, Cynthia Tallant, Shaima Hashem, Octovia P. Monteiro, Jason R. Thomas, Markus Schirle, Stefan Knapp, Brian D. Marsden, Oleg Fedorov, Chas Bountra, Benedikt M. Kessler, Paul E. Brennan
Bromodomain-containing proteins are epigenetic modulators involved in a wide range of cellular processes, from physiological 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, via copper-catalyzed alkyne azide coupling, to an alkyne handle on the probe allowed in-gel visualization and selective pull-down of the desired bromodomains using both recombinant and endogenous proteins.


Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD grant no. 115766], Wellcome [106169/ZZ14/Z], MRC Proximity to Discovery


Email Address of Submitting Author


University of Oxford


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

no conflict of interest