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PDBsum entry 4z93
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Transcription
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PDB id
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4z93
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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-Based design of γ-Carboline analogues as potent and specific bet bromodomain inhibitors.
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Authors
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X.Ran,
Y.Zhao,
L.Liu,
L.Bai,
C.Y.Yang,
B.Zhou,
J.L.Meagher,
K.Chinnaswamy,
J.A.Stuckey,
S.Wang.
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Ref.
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J Med Chem, 2015,
58,
4927-4939.
[DOI no: ]
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PubMed id
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Abstract
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Small-molecule inhibitors of bromodomain and extra terminal proteins (BET),
including BRD2, BRD3, and BRD4 proteins have therapeutic potential for the
treatment of human cancers and other diseases and conditions. In this paper, we
report the design, synthesis, and evaluation of γ-carboline-containing
compounds as a new class of small-molecule BET inhibitors. The most potent
inhibitor (compound 18, RX-37) obtained from this study binds to BET bromodomain
proteins (BRD2, BRD3, and BRD4) with Ki values of 3.2-24.7 nM and demonstrates
high selectivity over other non-BET bromodomain-containing proteins. Compound 18
potently and selectively inhibits cell growth in human acute leukemia cell lines
harboring the rearranged mixed lineage leukemia 1 gene. We have determined a
cocrystal structure of 18 in complex with BRD4 BD2 at 1.4 Å resolution, which
provides a solid structural basis for the compound's high binding affinity and
for its further structure-based optimization. Compound 18 represents a promising
lead compound for the development of a new class of therapeutics for the
treatment of human cancer and other conditions.
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