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PDBsum entry 4wiv
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Transcription/transcription inhibitor
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PDB id
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4wiv
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References listed in PDB file
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Key reference
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Title
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Biased multicomponent reactions to develop novel bromodomain inhibitors.
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Authors
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M.R.Mckeown,
D.L.Shaw,
H.Fu,
S.Liu,
X.Xu,
J.J.Marineau,
Y.Huang,
X.Zhang,
D.L.Buckley,
A.Kadam,
Z.Zhang,
S.C.Blacklow,
J.Qi,
W.Zhang,
J.E.Bradner.
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Ref.
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J Med Chem, 2014,
57,
9019-9027.
[DOI no: ]
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PubMed id
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Abstract
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BET bromodomain inhibition has contributed new insights into gene regulation and
emerged as a promising therapeutic strategy in cancer. Structural analogy of
early methyl-triazolo BET inhibitors has prompted a need for structurally
dissimilar ligands as probes of bromodomain function. Using fluorous-tagged
multicomponent reactions, we developed a focused chemical library of bromodomain
inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar
biochemical IC50. Iterative synthesis and biochemical assessment allowed
optimization of novel BET bromodomain inhibitors based on an
imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd
of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally,
compound 32 shows potency against TAF1, a bromodomain-containing transcription
factor previously unapproached by discovery chemistry. Compound 32 was
cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This
research showcases new applications of fluorous and multicomponent chemical
synthesis for the development of novel epigenetic inhibitors.
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