AS-99 is a first-in-class, potent, and selective inhibitor of the ASH1L histone methyltransferase, exhibiting anti-leukemic activity with an IC50 value of 0.79 µM and a Kd of 0.89 µM. It inhibits cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and effectively reduces leukemia burden in vivo.