Identification of a Chemical Probe for Bromo and Extra C-Terminal Bromodomain Inhibition through Optimization of a Fragment-Derived Hit

被引：157

作者：

Fish, Paul V. ^{[1
]}

Filippakopoulos, Panagis ^{[2
]}

Bish, Gerwyn ^{[1
]}

Brennan, Paul E. ^{[2
]}

Bunnage, Mark E. ^{[1
]}

Cook, Andrew S. ^{[1
]}

Federov, Oleg ^{[2
]}

Gerstenberger, Brian S. ^{[3
]}

Jones, Hannah

Knapp, Stefan ^{[2
]}

Marsden, Brian ^{[2
]}

Nocka, Karl

Owen, Dafydd R. ^{[1
]}

Philpott, Martin ^{[2
]}

Picaud, Sarah ^{[2
]}

Primiano, Michael J.

Ralph, Michael J. ^{[1
]}

Sciammetta, Nunzio ^{[1
]}

Trzupek, John D.

机构：

[1] Pfizer Worldwide R&D, Pfizer Worldwide Med Chem, Sandwich CT13 9NJ, Kent, England

[2] Univ Oxford, Struct Genom Consortium, Nuffield Dept Clin Med, Oxford OX3 7DQ, England

[3] Pfizer Worldwide R&D, Pfizer Worldwide Med Chem, Groton, CT 06340 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 22期

基金：

英国惠康基金; 加拿大创新基金会;

关键词：

CHROMATIN; DISCOVERY; ACETYLATION;

D O I：

10.1021/jm3010515

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 brome 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.

引用

页码：9831 / 9837

页数：7

共 23 条

[21] How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers
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