In biochemical testing, ON 146040 inhibits PI3Kα/ PI3Kδ isoforms (IC ₅₀ ≈14 and 20 nM, respectively) without having a major effect on PI3Kβ/ PI3Kγ isoforms (IC ₅₀ ≈3 and 1 μM, respectively). ON 146040 is also found to inhibit Abl1 and several mutant versions of this kinase (IC ₅₀ <150 nM), although ON 146040 is not found to be active against the T315I mutant. ON 146040 represents the first dual PI3K and BCR-ABL inhibitor that targets the STAT3 and STAT5 pathways. ON 146040 disrupts the oncogenic activity of both STAT3 and STAT5 by targeting upstream activators, including PI3K α and δ isoforms as well as wild type and mutant BCR-ABL. ON 146040 is highly potent in killing hematologic tumor cells with IC ₅₀ values in the 150 to 1,000 nM range. Following treatment with ON 146040, STAT3 and STAT5 phosphorylation are down-regulated in leukemia and myeloma cells.