IACS-010759 is a potent and selective inhibits oxidative phosphorylation with IC50 < 10 nM. It also binds to and inhibits complex I of the electron transport chain (NADH ubiquinone oxidoreductase), selectively depriving tumor cells of nutrients and energy, inhibiting nucleotide and amino acid production, and induces autophagy.
OxPhos (oxidative phosphorylation) is an energy-efficient way of synthesizing ATP in the mitochondria which is a predominant pathway in CLL (chronic lymphocytic leukemia) for energy production and is further augmented in the presence of the stromal microenvironment. IACS-010759, currently in clinical development, is a small-molecule, orally bioavailable OxPhos inhibitor that targets mitochondrial complex I at low nanomolar levels. Treatment of primary CLL cells with 100 nM IACS-010759 greatly inhibited OxPhos but caused only minor cell death at 24 and 48 h. In 100 nM IACS-010759-treated CLL cells, basal OCR (oxygen consumption rate, a measure of OxPhos) was greatly inhibited followed by a drastic decrease in spare respiratory capacity (after addition of FCCP, a kind of uncoupler) compared with the untreated control. CLL cells were incubated with 100 nM IACS-010759 for 24 h (n = 19) and 48 h (n = 6). The ribonucleotide pools decreased at both time points upon drug treatment. ATP concentrations in CLL cells from these patients ranged from 693 to 5267 μM with a mean of 2775 μM. This mean value decreased to 1652 μM after 24 h. At 48 h, the levels further decreased from 2124 to 943 μM. In CLL cells incubated with the combination of 100 nM IACS-010759 and 2-dG, the OCR was further and significantly reduced compared with controls and even compared with cells treated with IACS-010759 alone[1].
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