IACS-010759

SKU: orb1301875

Description

IACS-010759 is an orally active small molecule inhibitor targeting mitochondrial complex I (NADH:ubiquinone oxidoreductase). It disrupts oxidative phosphorylation and is utilized in both in vitro and in vivo research to study cancer metabolism, particularly in models reliant on oxidative phosphorylation for growth.

Research Area

Cell Biology, Metabolism Research

Key Properties

• CAS Number: 1570496-34-2
• MW: 562.6
• Purity: >98%
• Formula: C₂₅H₂₅F₃N₆O₄S
• SMILES: Cc1nc(nn1Cc1cccc(c1)N1CCC(CC1)S(C)(=O)=O)-c1nc(no1)-c1ccc(OC(F)(F)F)cc1
• Target: Energy production
• Solubility: Soluble in DMSO (25 mg/ml)

Bioactivity

• In Vivo:
  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 .
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• In Vitro:
  Treatment of primary CLL cells with IACS-010759 greatly inhibited oxidative phosphorylation (OxPhos) but caused only minor cell death at 24 and 48 h . KPS-tumor-derived murine cells were more sensitive to IACS-010759 compared to KP-tumor-derived cell lines . 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 .
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• Cell Research:
  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 .
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• Animal Research:
  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 .
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Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

H460, Inhibitor, IACS 010759, IACS 10759, IACS010759, IACS-010759, IACS10759, IACS-10759, orally, oxidative, OXPHOS, mitochondrial, Mitochondrial Metabolism, MitochondrialMetabolism, inhibit, Apoptosis, AML, complex, complex I of oxidative phosphorylation, phosphorylation

Compound Identifiers

PubChem CID

86711931