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PDBsum entry 6ton
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Transcription
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PDB id
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6ton
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References listed in PDB file
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Key reference
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Title
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Achieving in vivo target depletion through the discovery and optimization of benzimidazolone bcl6 degraders.
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Authors
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B.R.Bellenie,
K.J.Cheung,
A.Varela,
O.A.Pierrat,
G.W.Collie,
G.M.Box,
M.D.Bright,
S.Gowan,
A.Hayes,
M.J.Rodrigues,
K.N.Shetty,
M.Carter,
O.A.Davis,
A.T.Henley,
P.Innocenti,
L.D.Johnson,
M.Liu,
S.De klerk,
Y.V.Le bihan,
M.G.Lloyd,
P.C.Mcandrew,
E.Shehu,
R.Talbot,
H.L.Woodward,
R.Burke,
V.Kirkin,
R.L.M.Van montfort,
F.I.Raynaud,
O.W.Rossanese,
S.Hoelder.
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Ref.
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J Med Chem, 2020,
63,
4047-4068.
[DOI no: ]
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PubMed id
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Abstract
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Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of
germinal center B-cells, and hence BCL6 has been proposed as a therapeutic
target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we
report the discovery of a series of benzimidazolone inhibitors of the
protein-protein interaction between BCL6 and its co-repressors. A subset of
these inhibitors were found to cause rapid degradation of BCL6, and optimization
of pharmacokinetic properties led to the discovery of
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazo
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-o
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-on
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one
(CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model
following oral dosing.
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