Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)

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.