A novel inhibitor of the mitochondrial respiratory complex I with uncoupling properties exerts potent antitumor activity

Abstract Cancer cells are highly reliant on bioenergetic processes to support their growth and survival. Disrupting these metabolic pathways, notably by targeting the electron transport chain complexes (ETC-I to V) in the mitochondrial bioenergetic hub, has become an attractive therapeutic strategy. As a result, the pursuit of identifying clinically effective new inhibitors of the respiratory chain with minimized adverse effects stands as a significant objective. Here, we characterize a first in class OXPHOS inhibitor compound called MS-L6, which behaves as an inhibitor of ETC-I, combining inhibition of NADH oxidation and decoupling effect. MS-L6 is effective on both intact and fragmented mitochondrial membranes, indicating that its efficacy does not rely on its accumulation within the mitochondria. MS-L6 reduces ATP synthesis and induces a metabolic shift with increased glucose consumption and lactate production in cancer cell lines, while having minimal effects on primary hepatocytes. Its dose-dependently inhibits cell proliferation or induces cell death in a wide range of cancer cell lines, including B-cell and T-cell lymphoma, as well as pediatric sarcoma. Furthermore, ectopic expression of Saccharomyces cerevisiae NADH-dehydrogenase NDI1 partially restores the viability of lymphoma B cells treated with MS-L6, demonstrating that inhibition of NADH oxidation is key for its antitumoral activity. Finally, MS-L6 administration induces a robust inhibition of lymphoma tumor growth in two murine xenograft models, without significant toxicity. Therefore, our data unveil MS-L6 as an inhibitor of oxidative phosphorylation (OXPHOS), with an unexpected dual mechanism of action on the respiratory chain. Additionally, MS-L6 demonstrates potent antitumoral properties in preclinical models, positioning it as the pioneering member of a promising new drug class to be assessed for cancer therapy.