Acute myeloid leukemia (AML) is a heterogeneous group of aggressive hematological malignancies commonly associated with treatment resistance, high risk of relapse, and mitochondrial dysregulation. We identified six mitochondria-affecting compounds (PS compounds) that exhibit selective cytotoxicity against AML cells in vitro. Structure-activity relationship studies identified six analogs from two original scaffolds that had over an order of magnitude difference between LD50 in AML and healthy peripheral blood mononuclear cells. Mechanistically, all hit compounds reduced ATP and selectively impaired both basal and ATP-linked oxygen consumption in leukemic cells. Compounds derived from PS127 significantly upregulated production of reactive oxygen species (ROS) in AML cells and triggered ferroptotic, necroptotic, and/or apoptotic cell death in AML cell lines and refractory/relapsed AML primary samples. These compounds exhibited synergy with several anti-leukemia agents in AML, acute lymphoblastic leukemia (ALL), or chronic myelogenous leukemia (CML). Pilot in vivo efficacy studies indicate anti-leukemic efficacy in a MOLM14/GFP/LUC xenograft model, including extended survival in mice injected with leukemic cells pre-treated with PS127B or PS127E and in mice treated with PS127E at a dose of 5 mg/kg. These compounds are promising leads for development of future combinatorial therapeutic approaches for mitochondria-driven hematologic malignancies such as AML, ALL, and CML.
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The data in this study that support the findings of this study are available from the corresponding author upon reasonable request.
The code that supports the findings of this study are available from the corresponding author upon reasonable request.
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The study was supported by the CPRIT grant RR150044 and NIH NIGMS grant R35GM129294 to NVK and NIH NCI grants R01CA231364 and P50 CA100632 to MK. Computer-aided estimation of which regions of the chemical scaffold are relevant for cytotoxicity (L.A.S. and V.V.P.) was performed in the framework of the Russian Federation Fundamental Research Program for the long-term period for 2021–2030 (No. 122030100170-5).
The authors declare no competing interests.
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Panina, S.B., Pei, J., Baran, N. et al. Novel mitochondria-targeting compounds selectively kill human leukemia cells. Leukemia 36, 2009–2021 (2022). https://doi.org/10.1038/s41375-022-01614-0