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PDBsum entry 4z1s
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Signaling protein
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PDB id
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4z1s
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References listed in PDB file
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Key reference
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Title
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Discovery of benzotriazolo[4,3-D][1,4]diazepines as orally active inhibitors of bet bromodomains.
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Authors
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A.M.Taylor,
R.G.Vaswani,
V.S.Gehling,
M.C.Hewitt,
Y.Leblanc,
J.E.Audia,
S.Bellon,
R.T.Cummings,
A.Côté,
J.C.Harmange,
H.Jayaram,
S.Joshi,
J.M.Lora,
J.A.Mertz,
A.Neiss,
E.Pardo,
C.G.Nasveschuk,
F.Poy,
P.Sandy,
J.W.Setser,
R.J.Sims,
Y.Tang,
B.K.Albrecht.
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Ref.
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Acs Med Chem Lett, 2016,
7,
145-150.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of the bromodomains of the BET family, of which BRD4 is a member, has
been shown to decrease myc and interleukin (IL) 6 in vivo, markers that are of
therapeutic relevance to cancer and inflammatory disease, respectively. Herein
we report substituted benzo[b]isoxazolo[4,5-d]azepines and
benzotriazolo[4,3-d][1,4]diazepines as fragment-derived novel inhibitors of the
bromodomain of BRD4. Compounds from these series were potent and selective in
cells, and subsequent optimization of microsomal stability yielded
representatives that demonstrated dose- and time-dependent reduction of plasma
IL-6 in mice.
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