From Determinants of RUNX1/ETO Tetramerization to Small-Molecule Protein-Protein Interaction Inhibitors Targeting Acute Myeloid Leukemia

We identified the first small-molecule protein–protein interaction inhibitors of RUNX1/ETO tetramerization applying structure-based virtual screening guided by predicted hot spots and pockets in the interface. A 3D similarity screening revealed specific hot spot mimetics, one of which prevents the proliferation of RUNX1/ETO-dependent SKNO-1 cells at low micromolar concentration. Using solely a protein–protein complex structure to start with, this strategy can be the first step in any comparable structure-based endeavor to identify protein–protein interaction inhibitors.