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PDBsum entry 5eam
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Transcription/transcription inhibitor
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PDB id
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5eam
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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 optimization of a small molecule antagonist of the interaction between wd repeat-Containing protein 5 (wdr5) and mixed-Lineage leukemia 1 (mll1).
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Authors
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M.Getlik,
D.Smil,
C.Zepeda-Velázquez,
Y.Bolshan,
G.Poda,
H.Wu,
A.Dong,
E.Kuznetsova,
R.Marcellus,
G.Senisterra,
L.Dombrovski,
T.Hajian,
T.Kiyota,
M.Schapira,
C.H.Arrowsmith,
P.J.Brown,
M.Vedadi,
R.Al-Awar.
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Ref.
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J Med Chem, 2016,
59,
2478-2496.
[DOI no: ]
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PubMed id
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Abstract
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WD repeat-containing protein 5 (WDR5) is an important component of the
multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1).
Rearrangement of the MLL1 gene is associated with onset and progression of acute
myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may
result in new cancer therapeutics. Our previous work showed that binding of
small molecule ligands to WDR5 can modulate its interaction with MLL1,
suppressing MLL1 methyltransferase activity. Initial structure-activity
relationship studies identified
N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and
selective antagonists of this protein-protein interaction. Guided by crystal
structure data and supported by in silico library design, we optimized the
scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to
develop the first highly potent (Kdisp < 100 nM) small molecule antagonists
of the WDR5-MLL1 interaction and demonstrate that
N-(4-(4-methylpiperazin-1-yl)-3'-(morpholinomethyl)-[1,1'-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide
16d (OICR-9429) is a potent and selective chemical probe suitable to help
dissect the biological role of WDR5.
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