Skip to Content
Merck

Selective inhibition of BET bromodomains.

Nature (2010-09-28)
Panagis Filippakopoulos, Jun Qi, Sarah Picaud, Yao Shen, William B Smith, Oleg Fedorov, Elizabeth M Morse, Tracey Keates, Tyler T Hickman, Ildiko Felletar, Martin Philpott, Shonagh Munro, Michael R McKeown, Yuchuan Wang, Amanda L Christie, Nathan West, Michael J Cameron, Brian Schwartz, Tom D Heightman, Nicholas La Thangue, Christopher A French, Olaf Wiest, Andrew L Kung, Stefan Knapp, James E Bradner
ABSTRACT

Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
(+/-)-JQ1, ≥98% (HPLC)
SKU
Pack Size
Availability
Price
Quantity