AS-99 is a first-in-class, potent and selective ASH1L histone methyltransferase inhibitor ( IC 50 = 0.79 µM, K d = 0.89 µM) with anti-leukemic activity. AS-99 blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo.