Discovery of Novel Inhibitors Targeting the Menin-Mixed Lineage Leukemia Interface Using Pharmacophore- and Docking-Based Virtual Screening

Disrupting the interaction between mixed lineage leukemia
(MLL) fusion protein and menin provides a therapeutic approach for
MLL-mediated leukemia. Here, we aim to discover novel inhibitors targeting
the menin-MLL interface with virtual screening. Both structure-based
molecular docking and ligand-based pharmacophore models were established,
and the models used for compound screening show a remarkable ability
to retrieve known active ligands from decoy molecules. Verified by
a fluorescence polarization assay, five hits with novel scaffolds
were identified. Among them, DCZ_M123 exhibited potent inhibitory
activity with an IC50 of 4.71 ± 0.12 μM and
a KD of 14.70 ± 2.13 μM, and
it can effectively inhibit the human MLL-rearranged leukemia cells
MV4;11 and KOPN8 with GI50 values of 0.84 μM and
0.54 μM, respectively.