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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.
| Targets |
complex I of oxidative phosphorylation (OXPHOS)
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| 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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| Enzyme Assay |
Isolated mouse complex I assay[1]
Complex I was isolated from mouse heart mitochondria using an adaptation of the method of Sharpley and colleagues. The concentration of IACS-010759 in Fig. 1f was 60 nM. The NADH:decylubiquinone assay is described in Sharpley et al, and the APAD+ and H2O2 assays are described in Birrell et al. |
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| Cell Assay |
Generation of clonal cell lines resistant to IACS-010759[1]
H292 cells (1 × 106 cells/plate) were seeded in 15-cm dishes in galactose growth medium and treated with 1 nM IACS-010759 (IC65) for 3 weeks, followed by exposure to 8 nM IACS-010759 (IC95) until resistant clones emerged. Twenty-six resistant clones were isolated from four independent experiments and were seeded at 5 × 103 cells/well in 96-well plates in 100 µl galactose growth medium. After cells became fully attached, IACS-010759 or rotenone was added to a final concentration of 370 nM to 18 pM for 3 d. Plates were scanned in the IncuCyte live-cell analysis system before analysis via Hoechst and PI. Subsequently, both Hoechst and PI using an Operetta high-content imaging system. RNA-seq was conducted on the parental line and 12 resistant clones, uncovering a single nonsynonymous, heteroplasmic (35–50%), recurrent mutation in the mitochondrial-encoded gene MT-ND1 in 9 of the 12 resistant clones that conferred the L55F (T3469C) amino acid change. Paired-end reads were initially aligned to transcript sequences of complex I genes with Bowtie 2 (ref.53), and the aligned fragments were probabilistically assigned to transcripts using eXpress54. Variants from the reference genome were called using the ‘mpileup’ command in SAMtools. MutPred55 analysis of the L55F variant classifies the alteration as potentially pathogenic (MutPred score = 0.8); this alteration is found at a very low frequency in mtDNA sequences in Genebank (1:30,589 based on full-length mitochondrial genomes deposited in Genebank before 28 October 2015), suggesting it is unlikely to be a polymorphism. The mutation was confirmed in four of the resistant clones by cloning the MT-ND1 gene sequence and analyzing purified plasmid DNA via Sanger sequencing using the following primers: Forward: 5′-GTAAAACGACGGCCAGT-3′ and Reverse: 5′-AACAGCTATGACCATG-3′. |
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| Animal Protocol |
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| References |
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| Additional Infomation |
Tumor cells normally depend on both glycolysis and oxidative phosphorylation (OXPHOS) to provide the energy and macromolecule building blocks needed to enable continued tumor cell growth. Genetic or epigenetic inactivation of one of these two redundant pathways represents a metabolic vulnerability that should be susceptible to an inhibitor of the other pathway. Through an extensive medicinal chemistry campaign, IACS-10759 was identified as a potent inhibitor of complex I of oxidative phosphorylation. 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.
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| Molecular Formula |
C25H26CLF3N6O4S
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| Molecular Weight |
599.024953365326
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| Exact Mass |
598.137
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| Elemental Analysis |
C, 50.13; H, 4.38; Cl, 5.92; F, 9.51; N, 14.03; O, 10.68; S, 5.35
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| CAS # |
1807523-99-4
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| Related CAS # |
IACS-010759; 1570496-34-2; 1570496-34-2 (HCl); 1807524-00-0 (besylate); 1807524-05-5; 1807524-01-1 (mesylate)
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| PubChem CID |
91864637
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| Appearance |
Typically exists as white to off-white solids at room temperature
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
40
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| Complexity |
909
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LUSCFOVOISLXTM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H25F3N6O4S.ClH/c1-16-29-23(24-30-22(32-38-24)18-6-8-20(9-7-18)37-25(26,27)28)31-34(16)15-17-4-3-5-19(14-17)33-12-10-21(11-13-33)39(2,35)36;/h3-9,14,21H,10-13,15H2,1-2H3;1H
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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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