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PDBsum entry 4mr6
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Transcription/transcription inhibitor
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PDB id
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4mr6
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References listed in PDB file
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Key reference
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Title
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Rvx-208, An inhibitor of bet transcriptional regulators with selectivity for the second bromodomain.
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Authors
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S.Picaud,
C.Wells,
I.Felletar,
D.Brotherton,
S.Martin,
P.Savitsky,
B.Diez-Dacal,
M.Philpott,
C.Bountra,
H.Lingard,
O.Fedorov,
S.Müller,
P.E.Brennan,
S.Knapp,
P.Filippakopoulos.
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Ref.
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Proc Natl Acad Sci U S A, 2013,
110,
19754-19759.
[DOI no: ]
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PubMed id
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Abstract
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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.
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