Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5
Matthäus Getlik1, David Smil2, Carlos Zepeda-Velázquez1
1Drug Discovery Program, Ontario Institute for Cancer Research , 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.
Abstract:
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.
Insights
Researchers developed novel small molecules targeting the WDR5-MLL1 interaction, crucial in certain leukemias. These potent antagonists, like OICR-9429, offer new avenues for cancer therapeutics by inhibiting MLL1 methyltransferase activity.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- WD repeat-containing protein 5 (WDR5) is integral to the MLL1 complex, vital for activating mixed-lineage leukemia 1 (MLL1).
- MLL1 gene rearrangements are implicated in acute myeloid and lymphoblastic leukemias, highlighting WDR5-MLL1 as a therapeutic target.
Purpose of the Study:
- To develop potent and selective small molecule antagonists of the WDR5-MLL1 protein-protein interaction.
- To identify a chemical probe for investigating the biological role of WDR5 in cancer.
Main Methods:
- Structure-activity relationship (SAR) studies of N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides.
- In silico library design and optimization guided by crystal structure data.
- Development and characterization of novel small molecule antagonists.
Main Results:
- Identified potent and selective benzamide derivatives as WDR5-MLL1 interaction antagonists.
- Optimized scaffold led to compounds with Kdisp < 100 nM.
- Compound 16d (OICR-9429) demonstrated high potency and selectivity, suitable as a chemical probe.
Conclusions:
- Small molecule ligands binding to WDR5 can effectively suppress MLL1 methyltransferase activity.
- OICR-9429 represents a significant advancement in targeting the WDR5-MLL1 interaction for potential cancer therapy.
- This study provides a valuable tool for further research into WDR5's biological functions.
