IACS-010759 is an orally bioavailable inhibitor of complex I of oxidative phosphorylation of the mitochondrial electron transport chain.

Treatment of primary CLL cells with IACS-010759 greatly inhibited oxidative phosphorylation (OxPhos) but caused only minor cell death at 24 and 48 h [1]. KPS-tumor-derived murine cells were more sensitive to IACS-010759 compared to KP-tumor-derived cell lines [2]. Established AML cell lines were exposed to a range of IACS-010759 concentrations for 3–7 d, resulting in reduced viability with EC50 values of<3nM [3].

In mice following intravenous (0.3mg per kg body weight (mg/kg)) and oral (1mg/kg) administration, IACS-010759 was characterized by low plasma clearance with a high volume of distribution, resulting in a prolonged terminal half-life (>24h) of IACS-010759 with sustained levels of compound in the plasma following oral dosing. Treatment with IACS-010759 at the 5 or 10mg/kg dose resulted in tumor regression with minimal body weight loss, whereas IACS-010759 at the 25mg/kg dose was not tolerated, and body weight loss, lethargy, and hypothermia were observed [3].

CLL cells were incubated with either dimethyl sulfoxide (control) or IACS-010759 (100 nM) for 24 h. A total of 10^6 cells were stained with MitoSOX Red and tetramethylrhodamine ethyl ester perchlorate and were analyzed using flow cytometry for mitochondrial reactive oxygen species (ROS) and mitochondrial outer membrane potential, respectively [1].

OCI-AML3 cells were expanded in RPMI medium + 5% or 10% fetal bovine serum (FBS) until ≥150 million cells were present. For OCI-AML3, 2 million cells in 200 μl of saline were injection into the tail vein of NSG mice. For the patient-derived models, 4030094 and S6-AP, cells were harvested from mice with advanced disease or resuscitated from frozen vials, washed and resuspended at 5 x 10^6 cells/ml in PBS. Mice were irradiated for 24 hours at 250 cGY before orthotopic implantation of 1 x 10^6 cells suspended in 200 μl of saline were into the tail vein of 6- to 8-week old female NSG mice. For OCI-AML3, treatment began when whole body luminescence averaged 5 x 10^7. For model 4030094, treatment for the efficacy began when animals reached 10% burden and for the PK/PD studies when the animals reached 80% disease burden as measured by human and mouse CD45 and viability (DAPI 62248) staining followed by flow cytometry with a Fortessa flow cytometer. Mice were randomized based on luminescence for the OCI-AML3 model and by disease burden (hCD45+) for the patient-derived xenograft. Cohorts of mice were sacrificed 21 days after study drug initiation to collect spleen and bone marrow or followed for overall survival while continuing study drug [3].