Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 4, Issue 3, Pages 353-357Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml300467n
Keywords
WDR5; MLL; SET1 methyltransferase complex; peptide binding site; small molecule antagonists
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Funding
- Canadian Institutes for Health Research, Genome Canada [1097737]
- Canadian Foundation for Innovation
- Ontario Innovation Trust
- Ontario Ministry for Research and Innovation
- Wellcome Trust
- AbbVie
- Eli Lilly Canada
- GlaxoSmithKline
- Novartis
- Pfizer
- Takeda
- Government of Ontario through the Ontario Ministry of Economic Development and Innovation
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The WD40-repeat protein WDRS 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 mu M), leading to identification of more potent antagonist 47 (K-dis = 0.3 mu M).
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