Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 6, Pages 2478-2496Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01630
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Funding
- Ontario Institute for Cancer Research by Government of Ontario through the Ontario Ministry of Economic Development and Innovation
- Structural Genomics Consortium from AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA)
- Janssen
- Merck Co.
- Novartis Pharma AG
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
- Natural Sciences and Engineering Research Council of Canada
- National Research Council Canada
- Canadian Institutes of Health Research
- Province of Saskatchewan
- Western Economic Diversification Canada
- University of Saskatchewan
- CONACyT
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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-S substituents. This allowed us to develop the first highly potent (K-disp < 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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