In vitro activity: IACS-10759 was identified as a potent and orally bioavailable inhibitor of complex I of oxidative phosphorylation (OXPHOS). In isolated mitochondria or permeabilized cells, ATP production or oxygen consumption was inhibited at single digit nM concentrations in the presence of malate/glutamate, but not succinate. More directly, IACS-10759 inhibited the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations. Using genetic and pharmacological approaches, the specific complex I subunit inhibited by IACS-10759 has been identified and the mechanism of complex I inhibition is being investigated. Importantly, IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species and achieved significant in vivo efficacy with daily oral dosing of 10-25 mg/kg. Specifically, there was a>50 day extension of median survival in an orthotopic AML cell line xenograft and robust regression in DLBCL and GBM xenograft models. In light of these results, as well as its drug like profile IACS-10759 has entered IND enabling studies with first-in-human studies targeted for third quarter of 2015.

Kinase Assay: IACS-10759 inhibits the conversion of NADH to NAD+ in an immunoprecipitated complex I assay at low nM concentrations.

IACS-10759 is orally bioavailable with excellent physicochemical properties in preclinical species and achieves significant in vivo efficacy with daily oral dosing of 10-25 mg/kg. There is a>50 day extension of median survival in an orthotopic AML cell line xenograft and robust regression in DLBCL and GBM xenograft models.

[1] Nat Med. 2018 Jul;24(7):1036-1046.

[2] Cancer Res 2015;75(15 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2015-4380.