ND-646 |
| Katalog-Nr.GC32706 |
ND-646 ist ein oral verfügbarer und sterischer Inhibitor der Acetyl-CoA-Carboxylase (ACC) mit IC50-Werten von 3,5 nM und 4,1 nM für rekombinante hACC1 und hACC2.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1434639-57-2
Sample solution is provided at 25 µL, 10mM.
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ND-646 is an orally bioavailable and steric inhibitor of acetyl-CoA carboxylase (ACC) with IC50s of 3.5 nM and 4.1 nM for recombinant hACC1 and hACC2, respectively.
ND-646 inhibits both ACC1 and ACC2 and therefore precludes the ability of ACC2 to compensate for ACC1 inhibition. ND-646 inhibits dimerization of recombinant human ACC2 BC domain (hACC2-BC) under native conditions; hACC2-BC migrates as a dimer in its absence and a monomer in its presence. In cell free systems, ND-646 inhibits enzymatic activity of recombinant human ACC1 (hACC1) with an IC50 of 3.5 nM and recombinant human ACC2 (hACC2) with an IC50 of 4.1 nM[1].
To explore the impact of chronic ND-646 treatment on NSCLC tumor growth and to determine the efficacy of twice-daily dosing, athymic nude mice bearing established A549 subcutaneous tumors are treated orally with either vehicle twice daily (BID), 25 mg/kg ND-646 once daily (QD), 25 mg/kg ND-646 BID or 50 mg/kg ND-646 QD for 31 days. ND-646 at 25 mg/kg QD is ineffective at inhibiting tumor growth. However, ND-646 administered at 25 mg/kg BID or 50 mg/kg QD significantly inhibits subcutaneous A549 tumor growth. ND-646 is well tolerated throughout the treatment period, with no significant weight loss occurring after chronic ND-646 dosing, suggesting that the maximum tolerated dose (MTD) has not been reached. Mice are sacrificed at 1 hr post final dose and tissues are either prepared for immunohistochemistry (IHC) or immunoblot analysis. Tumors treated with all doses of ND-646 have lost detection of P-ACC at 1 hr, demonstrating effective tumor penetration and acute ACC inhibition by ND-646. Notably, only at the doses of ND-646 that lead to significant tumor growth inhibition (25 mg/kg BID and 50 mg/kg QD) is significant elevation of P-EIF2αS51 expression observed in tumor lysates[1].
[1]. Svensson RU, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med. 2016 Oct;22(10):1108-1119.
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Cell experiment: |
A549, H460, H157 and H1355 cells are tested for Mycoplasma and are deemed negative. Cells are grown in DMEM plus 10% fetal bovine serum. ACC1-KO clones are maintained in 10% FBS+addition of 200 μM palmitate every 3 days. For proliferation assays via cell counts, cells are plated into 24 well plates in triplicate at 2E4 cells/well and the following day treated with either DMSO vehicle or ND-608 or ND-646. Cell counts are recorded at days 1, 3, 5 and 7-post treatment. For delipidated media, cells are first seeded in media containing regular 10% FBS and the following day are switched into media containing 20% delipidated FBS upon treatment. Viability assays are performed using either a WST-1 viability assay or Cyquant in 96 well culture plates[1]. |
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Animal experiment: |
Mice[1] Subcutaneous tumor studies: For ACC1-KO studies, 8 week old athymic female nude mice are injected subcutaneously into the hind flanks with 2E6 cells of either WT or ACC1-KO luciferase expressing clones in a volume of 200 μL and imaged by BLI 20 mins after injection. Mice undergo BLI weekly for a period of 42 days (A549) and 49 days (H157), then mice are sacrificed and tumors are dissected and weighed. For ND-646 subcutaneous studies, female athymic nude mice are injected subcutaneously into the hind flanks with 5E6 A549 cells. Tumor growth is measured daily using digital calipers and volumes are calculated. Tumor prevention studies begin at 11 days post tumor cell injection. Mice are randomized into their treatment groups based on similar average tumor volumes. The average tumor volume at the initiation of treatment is 40 mm3. Mice are dosed orally (Per OS) once or twice a day with either a vehicle solution or ND-646 at either 25 mg/kg or 50 mg/kg (0.9% NaCl, 1% Tween 80, 0.5% methylcellulose). At the end of the study, mice are euthanized 1hr post final dose. |
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References: [1]. Svensson RU, et al. Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med. 2016 Oct;22(10):1108-1119. |
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| Cas No. | 1434639-57-2 | SDF | |
| Canonical SMILES | O=C(N)C(C)(C)N(C(N(C[C@@H](C1=CC=CC=C1OC)OC2CCOCC2)C3=C4C(C)=C(C5=NC=CO5)S3)=O)C4=O | ||
| Formula | C28H32N4O7S | M.Wt | 568.64 |
| Löslichkeit | DMSO : ≥ 100 mg/mL (175.86 mM) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7586 mL | 8.7929 mL | 17.5858 mL |
| 5 mM | 351.7 μL | 1.7586 mL | 3.5172 mL |
| 10 mM | 175.9 μL | 879.3 μL | 1.7586 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
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μL
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Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
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- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 34 reference(s) in Google Scholar.)
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