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

将初级CLL细胞处理IACS-010759明显抑制了氧化磷酸化(OxPhos)，但在24和48小时时仅造成了轻微的细胞死亡[1]。与KP-肿瘤衍生细胞系相比，KPS-肿瘤衍生的鼠类细胞对IACS-010759更敏感[2]。已建立的AML细胞系暴露于不同浓度的IACS-010759下3-7天，导致细胞活力降低，其EC50值<3nM[3]。

在小鼠中，通过静脉注射（0.3mg/kg）和口服（1mg/kg）给药后，IACS-010759显示出低血浆清除率和高分布容积，导致其在口服给药后在血浆中的终末半衰期延长（>24小时），维持了IACS-010759的持续血浆水平。以5或10mg/kg的剂量治疗时，IACS-010759能导致肿瘤退缩，并且体重损失最小；然而，以25mg/kg的剂量给药时，则不被耐受，并观察到体重减轻、嗜睡和低体温现象[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].