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PDBsum entry 5n1v
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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 pyrazolo[1,5-A]pyrimidine b-Cell lymphoma 6 (bcl6) binders and optimization to high affinity macrocyclic inhibitors.
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Authors
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W.Mccoull,
R.D.Abrams,
E.Anderson,
K.Blades,
P.Barton,
M.Box,
J.Burgess,
K.Byth,
Q.Cao,
C.Chuaqui,
R.J.Carbajo,
T.Cheung,
E.Code,
A.D.Ferguson,
S.Fillery,
N.O.Fuller,
E.Gangl,
N.Gao,
M.Grist,
D.Hargreaves,
M.R.Howard,
J.Hu,
P.D.Kemmitt,
J.E.Nelson,
N.O'Connell,
D.B.Prince,
P.Raubo,
P.B.Rawlins,
G.R.Robb,
J.Shi,
M.J.Waring,
D.Whittaker,
M.Wylot,
X.Zhu.
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Ref.
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J Med Chem, 2017,
60,
4386-4402.
[DOI no: ]
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PubMed id
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Abstract
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Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6)
and corepressors has been implicated as a therapeutic target in diffuse large
B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6
inhibitors are critical to test this hypothesis. We identified a
pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in
parallel with a virtual screen. Using structure-based drug design, binding
affinity was increased 100000-fold. This involved displacing crystallographic
water, forming new ligand-protein interactions and a macrocyclization to favor
the bioactive conformation of the ligands. Optimization for slow off-rate
constant kinetics was conducted as well as improving selectivity against an
off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized
to afford highly selective probe molecules. Only weak antiproliferative effects
were observed across a number of DLBCL lines and a multiple myeloma cell line
without a clear relationship to BCL6 potency. As a result, we conclude that the
BCL6 hypothesis in DLBCL cancer remains unproven.
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