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An Activity‐Based Probe Targeting Non‐Catalytic, Highly Conserved Amino Acid Residues within Bromodomains
Author(s) -
D'Ascenzio Melissa,
Pugh Kathryn M.,
Konietzny Rebecca,
Berridge Georgina,
Tallant Cynthia,
Hashem Shaima,
Monteiro Octovia,
Thomas Jason R.,
Schirle Markus,
Knapp Stefan,
Marsden Brian,
Fedorov Oleg,
Bountra Chas,
Kessler Benedikt M.,
Brennan Paul E.
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201807825
Subject(s) - bromodomain , druggability , small molecule , biochemistry , lysine , epigenetics , chemistry , amino acid , tyrosine , transcription factor , computational biology , biology , microbiology and biotechnology , gene
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.