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PDBsum entry 4ia9
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Transcription
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PDB id
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4ia9
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References listed in PDB file
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Key reference
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Title
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Synthesis, Optimization, And evaluation of novel small molecules as antagonists of wdr5-Mll interaction.
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Authors
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Y.Bolshan,
M.Getlik,
E.Kuznetsova,
G.A.Wasney,
T.Hajian,
G.Poda,
K.T.Nguyen,
H.Wu,
L.Dombrovski,
A.Dong,
G.Senisterra,
M.Schapira,
C.H.Arrowsmith,
P.J.Brown,
R.Al-Awar,
M.Vedadi,
D.Smil.
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Ref.
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ACS Med Chem Lett, 2013,
4,
353-357.
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PubMed id
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Abstract
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The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity
of MLL complexes and fully activating their methyltransferase function. MLL
complexes, the trithorax-like family of SET1 methyltransferases, catalyze
trimethylation of lysine 4 on histone 3, and they have been widely implicated in
various cancers. Antagonism of WDR5 and MLL subunit interaction by small
molecules has recently been presented as a practical way to inhibit activity of
the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl)
benzamides were reported as potent and selective antagonists of such an
interaction. Here, we describe the protein crystal structure guided optimization
of prototypic compound 2 (K dis = 7 μM), leading to identification of more
potent antagonist 47 (K dis = 0.3 μM).
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