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Acute myeloid leukemia (AML) is a deadly hematological malignancy characterized by oncogenic translational addiction that results in over-proliferation and apoptosis evasion of leukemia cells. Various chemo- and targeted therapies aim to reverse this hallmark, but most show only modest efficacy. Here we report a single oral pill containing a low-dose triple small molecule-based cocktail, a highly active anti-cancer therapy (HAACT) with unique mechanisms that can effectively control AML. The cocktail comprises oncogenic translation inhibitor HHT, drug efflux pump P-gpi ENC and anti-apoptotic protein Bcl-2i VEN. Mechanistically, the cocktail can potently kill both leukemia stem cells (LSC) and bulk leukemic cells via co-targeting oncogenic translation, apoptosis machinery, and drug efflux pump, resulting in deep and durable remissions of AML in diverse model systems. We also identified EphB4/Bcl-xL as the cocktail response biomarkers. Collectively, our studies provide proof that a single pill containing a triple combination cocktail might be a promising avenue for AML therapy.

Acute myeloid leukemia harboring internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3-ITD AML) is a subset of highly aggressive malignancies with poor clinical outcome. Despite some advances in the development of FLT3 tyrosine kinase inhibitors (FLT3 inhibitors), most of FLT3-ITD AML patients suffer from lethal disease relapse, suggesting the requirement of novel targets and agents. Here we describe a natural small molecule, triptonide that can efficiently inhibit FLT3-ITD-driven AML in vitro and in vivo. Mechanistically, triptonide targeted Hedgehog/FLT3 signaling by inhibiting its critical effectors, which are GLI2, c-Myc and FLT3 and induced apoptosis of FLT3-ITD-driven leukemia cells. In addition, we also observed that triptonide activated tumor suppressor p53. In vivo, triptonide treatment markedly suppressed lethal FLT3-ITD-driven AML with good tolerance and prolonged survival time in orthotopic mouse model. Our studies identify Hedgehog/FLT3 axis as a novel target for treating FLT3-ITD-driven leukemia and demonstrate that triptonide is an active lead compound that can kill FLT3-ITD-driven leukemia cells.

Proto-oncogene Myc, a key transcription factor, is frequently deregulated in human leukemia with aggressive and poor clinical outcome, but the development of MYC inhibitors remains challenging due to MYC helix-loop-helix topology lacking druggable domains. Here we describe a novel oral active small molecule analog of berbamine, tosyl chloride-berbamine (TCB), that efficiently eliminates MYC-positive leukemia in vitro and in vivo. Mechanistically, TCB potently reduced MYC protein by inhibiting CaMKIIγ, a critical enzyme that stabilizes MYC protein, and induces apoptosis of MYC-positive leukemia cells. In vivo, oral administration of TCB markedly eliminated lethal MYC-positive acute lymphoblastic leukemia (ALL) with well tolerability in orthotopic mouse model. Our studies identify CaMKIIγ/Myc axis as a valid target for developing small molecule-based new therapies for treating MYC-mediated leukemia and demonstrate that TCB is an orally active analog of berbamine that kills MYC-positive leukemia cells.