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PDBsum entry 5mw2
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Transcription
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PDB id
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5mw2
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References listed in PDB file
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Key reference
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Title
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Chemically induced degradation of the oncogenic transcription factor bcl6.
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Authors
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N.Kerres,
S.Steurer,
S.Schlager,
G.Bader,
H.Berger,
M.Caligiuri,
C.Dank,
J.R.Engen,
P.Ettmayer,
B.Fischerauer,
G.Flotzinger,
D.Gerlach,
T.Gerstberger,
T.Gmaschitz,
P.Greb,
B.Han,
E.Heyes,
R.E.Iacob,
D.Kessler,
H.Kölle,
L.Lamarre,
D.R.Lancia,
S.Lucas,
M.Mayer,
K.Mayr,
N.Mischerikow,
K.Mück,
C.Peinsipp,
O.Petermann,
U.Reiser,
D.Rudolph,
K.Rumpel,
C.Salomon,
D.Scharn,
R.Schnitzer,
A.Schrenk,
N.Schweifer,
D.Thompson,
E.Traxler,
R.Varecka,
T.Voss,
A.Weiss-Puxbaum,
S.Winkler,
X.Zheng,
A.Zoephel,
N.Kraut,
D.Mcconnell,
M.Pearson,
M.Koegl.
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Ref.
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Cell Rep, 2017,
20,
2860-2875.
[DOI no: ]
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PubMed id
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Abstract
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The transcription factor BCL6 is a known driver of oncogenesis in lymphoid
malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its
interaction with transcriptional repressors interferes with the oncogenic
effects of BCL6. We used a structure-based drug design to develop highly potent
compounds that block this interaction. A subset of these inhibitors also causes
rapid ubiquitylation and degradation of BCL6 in cells. These compounds display
significantly stronger induction of expression of BCL6-repressed genes and
anti-proliferative effects than compounds that merely inhibit co-repressor
interactions. This work establishes the BTB domain as a highly druggable
structure, paving the way for the use of other members of this protein family as
drug targets. The magnitude of effects elicited by this class of BCL6-degrading
compounds exceeds that of our equipotent non-degrading inhibitors, suggesting
opportunities for the development of BCL6-based lymphoma therapeutics.
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