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The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.

Original publication

DOI

10.1021/jm3010515

Type

Journal article

Journal

Journal of medicinal chemistry

Publication Date

08/11/2012

Volume

55

Pages

9831 - 9837

Addresses

Pfizer Worldwide Medicinal Chemistry, Pfizer Worldwide R&D , Ramsgate Road, Sandwich CT13 9NJ, United Kingdom.

Keywords

Humans, Sulfonamides, Nuclear Proteins, Transcription Factors, Molecular Probes, Crystallography, X-Ray, Molecular Structure, Protein Binding, Structure-Activity Relationship, Models, Molecular, Quinazolinones