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| 25mg |
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Purity: ≥98%
IACS-10759 HCl (IACS10759; IACS-010759) was identified as a potent and orally bioavailable inhibitor of complex I of oxidative phosphorylation (OXPHOS) with anticancer activity. 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.
| ln Vitro |
IACS-010759 hydrochloride (10, 30, 100 nM; for 4 or 5 days) lowers the viability of primary AML and promotes apoptosis [1]. IACS-010759 hydrochloride (0.001, 0.01, 0.1, 1, 10, 100, 1000 nM; 72 h) substantially suppresses OCR and galactose-dependent H460 cell survival with practically the same IC50 value of 1.4 nM[1]. IACS-010759 hydrochloride has similar action in mouse (average IC50=5.6 nM), rat (IC50=12.2 nM) and cynomolgus monkey (IC50=8.7 nM) cell lines [1].
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| ln Vivo |
In mice with NB-1 (PGD null) subcutaneous xenografts, IACS-010759 hydrochloride (5, 10, 25 mg/kg/day; oral; for 21 days) at dosages of 5 or 10 mg/kg caused tumor reduction, negligible weight loss, and intolerance to the 25 mg/kg dose [1]. Less frequent dosing regimens (Q2D or Q3D) may somewhat enhance survival, but IACS-010759 hydrochloride (10?mg/kg; oral; QD (daily) or QD×5 (5 d on/2 d off); for 35 d) prolonged median survival from 28 days to over 60 days [1]. With a high volume of distribution and low plasma clearance, IACS-010759 hydrochloride (0.3 mg/kg for intravenous; 1 mg/kg for oral) has a prolonged terminal half-life (>24 hours) [1].
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| References |
[1]. Protopopova M. IACS-10759: A novel OXPHOS inhibitor which selectively kill tumors with metabolic vulnerabilities. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2015-4380
[2]. Jennifer R Molina, et al. An inhibitor of oxidative phosphorylation exploits cancer vulnerability. Nat Med. 2018 Jul;24(7):1036-1046. |
| Molecular Formula |
C25H26CLF3N6O4S
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| Molecular Weight |
599.03
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| CAS # |
1807523-99-4
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| Related CAS # |
IACS-010759;1570496-34-2
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| SMILES |
Cl.S(C)(C1CCN(C2C=CC=C(CN3C(C)=NC(C4=NC(C5C=CC(=CC=5)OC(F)(F)F)=NO4)=N3)C=2)CC1)(=O)=O
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6694 mL | 8.3468 mL | 16.6937 mL | |
| 5 mM | 0.3339 mL | 1.6694 mL | 3.3387 mL | |
| 10 mM | 0.1669 mL | 0.8347 mL | 1.6694 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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