| 名称 | IACS-010759 |
| 描述 | IACS-010759 is an orally bioavailable inhibitor of complex I of oxidative phosphorylation of the mitochondrial electron transport chain. |
| 细胞实验 | 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]. |
| 动物实验 | 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]. |
| 体外活性 | 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]. |
| 体内活性 | 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]. |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | DMSO : 20 mg/mL (35.55 mM), Sonication is recommended.
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| 关键字 | OXPHOS | phosphorylation | complex | Apoptosis | mitochondrial | IACS-010759 | Inhibitor | orally | IACS 010759 | inhibit | H460 | Mitochondrial Metabolism | AML | IACS010759 | oxidative |
| 相关产品 | Stavudine | 5-Fluorouracil | Imeglimin hydrochloride | Acetylcysteine | Kaempferol | Myricetin | Sodium 4-phenylbutyrate | L-Ascorbic acid | Dextran sulfate sodium salt (MW 4500-5500) | Metronidazole | Sorafenib | Tributyrin |
| 相关库 | 经典已知活性库 | 神经退行性疾病化合物库 | 血液病分子库 | 抗癌临床化合物库 | 药物功能重定位化合物库 | 抑制剂库 | 抗衰老化合物库 | 已知活性化合物库 | 抗癌活性化合物库 | 抗癌药物库 |
United States
