IACS-010759 | Mitochondrial Complex I Inhibitor

IACS-010759 (1570496-34-2) is a potent (IC₅₀ = 1.1 nM isolated mouse complex I) and selective inhibitor of complex I of the mitochondrial electron transport chain (OXPHOS). IACS-010759 displayed in vivo efficacy in glycolysis-deficient glioblastoma and AML models without cytotoxicity to normal cells. The lack of cytotoxicity to normal cells, as opposed to other complex I inhibitors, is attributed to its unique binding location on complex I.² Complex I inhibition by IACS-010759 causes an ROS-induced decrease in the endogenous PP2A inhibitor CIP2A leading to cell death.³ It has also displayed potential in various chemotherapy-resistant cancer cell lines.^4-7

References/Citations:

1. Molina et al. (2018), An inhibitor of oxidative phosphorylation exploits cancer vulnerability; Nature Med. 24 1036
2. Tsuji et al. (2020), IACS-010759, a potent inhibitor of glycolysis-deficient hypoxic tumor cells, inhibits mitochondrial respiratory complex I through a unique mechanism; J. Biol. Chem. 295 7481
3. Cazzoli et al. (2023), Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition; Cell Rep. 42 112616
4. Gopal et al. (2019), A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma; Clin. Cancer Res. 25 6429
5. Stuani et al. (2021), Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia; J. Exp. Med. 218 e20200924
6. Evans et al. (2021), Oxidative Phosphorylation is a Metabolic Vulnerability in Chemotherapy-Resistant Triple-Negative Breast Cancer; Cancer Res. 81 5572
7. Fuhr et al. (2022), CD52 and OXPHOS – potential targets in ibrutinib-treated mantle cell lymphoma; Cell Death Discov. 8 505