The structure based design of dual HDAC/BET inhibitors as novel epigenetic probes

被引：58

作者：

Atkinson, Stephen J. ^{[1
]}

Soden, Peter E. ^{[1
]}

Angell, Davina C. ^{[1
]}

Bantscheff, Marcus ^{[2
]}

Chung, Chun-wa ^{[3
]}

Giblin, Kathryn A. ^{[1
]}

Smithers, Nicholas ^{[1
]}

Furze, Rebecca C. ^{[1
]}

Gordon, Laurie ^{[4
]}

Drewes, Gerard ^{[2
]}

Rioja, Inmaculada ^{[1
]}

Witherington, Jason ^{[1
]}

Parr, Nigel J. ^{[1
]}

Prinjha, Rab K. ^{[1
]}

机构：

[1] GlaxoSmithKline R&D, Epinova Discovery Performance Unit, Stevenage SG1 2NY, Herts, England

[2] GlaxoSmithKline R&D, Mol Discovery Res, Cellzome, Technol & Sci,Platform, D-69117 Heidelberg, Germany

[3] GlaxoSmithKline R&D, Mol Discovery Res, Computat & Struct Chem, Med Res Ctr, Stevenage SG1 2NY, Herts, England

[4] GlaxoSmithKline R&D, Mol Discovery Res, Screening & Compound Profiling, Med Res Ctr, Stevenage SG1 2NY, Herts, England

来源：

MEDCHEMCOMM | 2014年 / 5卷 / 03期

关键词：

CROSS-COUPLING REACTIONS; FRAGMENT-BASED DISCOVERY; HISTONE DEACETYLASES; SELECTIVE-INHIBITION; BET; CANCER; OPTIMIZATION; CATALYST; SERIES;

D O I：

10.1039/c3md00285c

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Herein we describe the design and synthesis of a dual active histone deacetylase (HDAC)/bromodomain and extra terminal (BET) small molecule toot inhibitor, DUAL946 (1). Exploiting our extensive epigenetic toolbox, we achieved the functionalisation of a BET active tetrahydroquinoline (THQ) core, with a hydroxamic acid HDAC inhibitor (HDACi) motif. Dual inhibition of BET and HDAC proteins was confirmed by in vitro biochemical and biophysical testing and through chemoproteomic competition experiments in cell lysates. This activity was translated into potent cellular activity in both immune and cancer cells.

引用

页码：342 / 351

页数：10

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