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PDBsum entry 4ybm
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Transcription/transcription inhibitor
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PDB id
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4ybm
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References listed in PDB file
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Key reference
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Title
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Structure-Guided design of iacs-9571, A selective high-Affinity dual trim24-Brpf1 bromodomain inhibitor.
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Authors
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W.S.Palmer,
G.Poncet-Montange,
G.Liu,
A.Petrocchi,
N.Reyna,
G.Subramanian,
J.Theroff,
A.Yau,
M.Kost-Alimova,
J.P.Bardenhagen,
E.Leo,
H.E.Shepard,
T.N.Tieu,
X.Shi,
Y.Zhan,
S.Zhao,
M.C.Barton,
G.Draetta,
C.Toniatti,
P.Jones,
M.Geck do,
J.N.Andersen.
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Ref.
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J Med Chem, 2016,
59,
1440-1454.
[DOI no: ]
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PubMed id
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Abstract
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The bromodomain containing proteins TRIM24 (tripartite motif containing protein
24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in
the epigenetic regulation of gene expression and have been implicated in human
cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and
BRPF1 is a scaffolding protein required for the assembly of histone
acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc
finger protein) was first identified as a recurrent fusion partner in leukemia
patients (8p11 chromosomal rearrangements). Here, we present the structure
guided development of a series of N,N-dimethylbenzimidazolone bromodomain
inhibitors through the iterative use of X-ray cocrystal structures. A unique
binding mode enabled the design of a potent and selective inhibitor 8i
(IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM
and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 =
50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality
chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in
vitro and in vivo.
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