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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.

Original publication

DOI

10.1038/nchembio.2080

Type

Journal article

Journal

Nat Chem Biol

Publication Date

07/2016

Volume

12

Pages

504 - 510

Keywords

Cell Line, Cell Proliferation, Chromatin, Histone Acetyltransferases, Humans, Molecular Structure, Nuclear Proteins, Protein Domains, Small Molecule Libraries, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcription Factors