KO-539 was identified using high-throughput virtual screening followed by structure-based optimization evidencing an IC50 of 22 nM for menin/MLL binding inhibition and a cellular activity at the nanomolar range on cell lines bearing MLL fusions with AF4, AF9, or ENL partners (either in AML or ALL cell models of MPAL), but at the micromolar range in non-MLL leukemic models. Here, KMT2A is linked to acute lymphoblastic leukemia.