Issue 3, 2014
From the journal:

MedChemComm

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

Stephen J. Atkinson,*a   Peter E. Soden,a   Davina C. Angell,a   Marcus Bantscheff,b   Chun-wa Chung,c   Kathryn A. Giblin,a   Nicholas Smithers,a   Rebecca C. Furze,a   Laurie Gordon,d   Gerard Drewes,b   Inmaculada Rioja,a   Jason Witherington,a   Nigel J. Parra  and  Rab K. Prinjhaa  

* Corresponding authors

a Epinova Discovery Performance Unit, GlaxoSmithKline R&D, Stevenage, Hertfordshire SG1 2NY, UK
E-mail: stephen.j.Atkinson@gsk.com
Fax: +44 (0)1438 764799
Tel: +44 (0)1438 745745

b Platform, Technology & Science, Cellzome, Molecular Discovery Research, GlaxoSmithKline R&D, Meyerhofstrasse 1, Heidelberg, Germany

c Computational & Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK

d Screening & Compound Profiling, Molecular Discovery Research, GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK

Abstract

Herein we describe the design and synthesis of a dual active histone deacetylase (HDAC)/bromodomain and extra terminal (BET) small molecule tool 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.

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

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Article information

DOI
https://doi.org/10.1039/C3MD00285C
Article type
Concise Article
Submitted
30 Sep 2013
Accepted
30 Dec 2013
First published
29 Jan 2014

Med. Chem. Commun., 2014,5, 342-351

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

S. J. Atkinson, P. E. Soden, D. C. Angell, M. Bantscheff, C. Chung, K. A. Giblin, N. Smithers, R. C. Furze, L. Gordon, G. Drewes, I. Rioja, J. Witherington, N. J. Parr and R. K. Prinjha, Med. Chem. Commun., 2014, 5, 342 DOI: 10.1039/C3MD00285C

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