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

Sarah Picaud1, Christopher Wells, Ildiko Felletar

  • 1Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ, United Kingdom.

Proceedings of the National Academy of Sciences of the United States of America
|November 20, 2013
PubMed

Insights

RVX-208 selectively inhibits the second bromodomain (BD2) of bromo and extraterminal (BET) proteins, impacting gene transcription. This study highlights the importance of BD1 in transcriptional regulation and demonstrates domain-specific targeting feasibility.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Drug Discovery

Background:

  • Bromodomains, particularly within the bromo and extraterminal (BET) family, are key regulators of gene transcription.
  • BET protein inhibitors show therapeutic potential but raise safety concerns due to their broad effects.
  • Targeting specific domains within BET proteins is proposed to improve safety and efficacy.

Purpose of the Study:

  • To investigate the domain specificity of the BET inhibitor RVX-208.
  • To elucidate the mechanism of action and transcriptional consequences of inhibiting specific BET bromodomains.
  • To assess the feasibility of domain-specific targeting within the BET family.

Main Methods:

  • Cocrystallography to determine binding modes of RVX-208.
  • Fluorescent recovery after photobleaching (FRAP) to assess chromatin displacement.
  • Gene expression analysis to evaluate transcriptional effects.

Main Results:

  • RVX-208 was identified as a specific inhibitor of the second bromodomain (BD2) of BET proteins.
  • RVX-208 effectively displaces BET proteins from chromatin.
  • Inhibition of BD2 alone resulted in only modest changes in BET-dependent gene transcription.

Conclusions:

  • Specific targeting of BET bromodomain 2 (BD2) is feasible.
  • The first bromodomain (BD1) plays a critical role in transcriptional regulation by BET proteins.
  • Domain-specific inhibition offers a strategy for modulating BET-dependent transcription with potentially improved safety profiles.
Keywords:
ApoA1epigeneticsmicroarraysmall molecule inhibitor

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