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. 2016 Jul;12(7):504-10.
doi: 10.1038/nchembio.2080. Epub 2016 May 9.

Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk

Sara Sdelci  1 , Charles-Hugues Lardeau  1   2 , Cynthia Tallant  3   4 , Freya Klepsch  1 , Björn Klaiber  1 , James Bennett  3   4 , Philipp Rathert  5 , Michael Schuster  1 , Thomas Penz  1 , Oleg Fedorov  3   4 , Giulio Superti-Furga  1   6 , Christoph Bock  1   7   8 , Johannes Zuber  5 , Kilian V M Huber  1   3   4 , Stefan Knapp  3   4   9 , Susanne Müller  3   4 , Stefan Kubicek  1   2
Affiliations

Mapping the chemical chromatin reactivation landscape identifies BRD4-TAF1 cross-talk

Sara Sdelci et al. Nat Chem Biol. 2016 Jul.

Abstract

Bromodomain-containing proteins of the BET family recognize histone lysine acetylation and mediate transcriptional activation of target genes such as the MYC oncogene. Pharmacological inhibitors of BET domains promise therapeutic benefits in a variety of cancers. We performed a high-diversity chemical compound screen for agents capable of modulating BRD4-dependent heterochromatization of a generic reporter in human cells. In addition to known and new compounds targeting BRD4, we identified small molecules that mimic BRD4 inhibition without direct engagement. One such compound was a potent inhibitor of the second bromodomain of TAF1. Using this inhibitor, we discovered that TAF1 synergizes with BRD4 to control proliferation of cancer cells, making TAF1 an attractive epigenetic target in cancers driven by MYC.

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