Mixed lineage leukemia (MLL) gene rearrangements cause ∼75% of acute leukemia in infants and 5-10% in children and adults with poor clinical outcomes. Protein-protein interactions (PPI) between frequent MLL fusion partners AF9/ENL and AF4 or histone methyltransferase DOT1L are drug targets for MLL-rearranged (MLL-r) leukemia. Sixty-seven quinoxiline compounds were synthesized and tested for their ability to inhibit such PPIs. Compounds 16, 17, 59, and 63 were found to be potent inhibitors with IC50 values of 0.35-1.5 μM. Structure-activity relationships are discussed. Potent inhibitors can suppress the expression of MLL target genes Myc and Meis1 and selectively block the proliferation of MLL-r and several other leukemia cells with EC50 values as low as 0.84 μM. Compound 17 exhibited significant antitumor activities in a mouse model of MLL-r leukemia without overt toxicities. It also showed favorable pharmacokinetics in mice. These results indicate that compound 17 is a promising pharmaceutical lead for the treatment of MLL-r leukemia.