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PMID: 24248379 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 110 ·No. 49 ·2013-12-03 ·Pages 19754-9

Picaud S, Wells C, Felletar I, Brotherton D, Martin S, Savitsky P, Diez-Dacal B, Philpott M, Bountra C, Lingard H, Fedorov O, Müller S, Brennan PE, Knapp S, Filippakopoulos P

Abstract

Bromodomains have emerged as attractive candidates for the development of inhibitors targeting gene transcription. Inhibitors of the bromo and extraterminal (BET) family recently showed promising activity in diverse disease models. However, the pleiotropic nature of BET proteins regulating tissue-specific transcription has raised safety concerns and suggested that attempts should be made for domain-specific targeting. Here, we report that RVX-208, a compound currently in phase II clinical trials, is a BET bromodomain inhibitor specific for second bromodomains (BD2s). Cocrystal structures revealed binding modes of RVX-208 and its synthetic precursor, and fluorescent recovery after photobleaching demonstrated that RVX-208 displaces BET proteins from chromatin. However, gene-expression data showed that BD2 inhibition only modestly affects BET-dependent gene transcription. Our data demonstrate the feasibility of specific targeting within the BET family resulting in different transcriptional outcomes and highlight the importance of BD1 in transcriptional regulation.

Keywords
ApoA1 epigenetics microarray small molecule inhibitor
MeSH Terms
Crystallization Fluorescence Recovery After Photobleaching Hep G2 Cells Humans Models, Molecular Molecular Structure Oligonucleotide Array Sequence Analysis Protein Binding Protein Structure, Tertiary/physiology Quinazolines/chemistry,pharmacology Quinazolinones Transcription Factors/antagonists & inhibitors,chemistry
Chemicals
Quinazolines Quinazolinones Transcription Factors apabetalone
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Picaud Sarah
Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.
Wells Christopher
Felletar Ildiko
Brotherton Deborah
Martin Sarah
Savitsky Pavel
Diez-Dacal Beatriz
Philpott Martin
Bountra Chas
Lingard Hannah
Fedorov Oleg
Müller Susanne
Brennan Paul E
Knapp Stefan
Filippakopoulos Panagis
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1310658110
Published
2013-12-03
Epub
2013-00-18
Pages
19754-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3856850
Subset
IM
Grants
Wellcome Trust · 092809/Z/10/Z · United Kingdom
Wellcome Trust · 095751/Z/11/Z · United Kingdom
Canadian Institutes of Health Research · Canada
Databases
GEO
GSE51143
PDB
4MR3, 4MR4, 4MR5, 4MR6
External Links
PubMed source DOI: 10.1073/pnas.1310658110 PMC Full Text View journal details
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