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Purity: ≥98%
| Targets |
ND-646 targets acetyl-CoA carboxylase (ACC) enzymes ACC1 and ACC2, which catalyze the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step in fatty acid synthesis. It acts as an allosteric inhibitor that prevents ACC subunit dimerization. ACC1 is primarily involved in cytosolic fatty acid synthesis, while ACC2 regulates mitochondrial fatty acid oxidation. By inhibiting both ACC isoforms, ND-646 disrupts cancer cell metabolism and suppresses de novo fatty acid synthesis.
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| ln Vitro |
ND-646 prevents both ACC1 and ACC2 from functioning, which means that ACC2 cannot make up for ACC1 inhibition. Recombinant human ACC2 BC domain (hACC2-BC) dimerization is inhibited by ND-646 in natural circumstances; hACC2-BC dimerization is absent. ND-646 functions as an enzyme in cell-free systems for the 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].
In vitro, ND-646 inhibits recombinant hACC1 and hACC2 with IC₅₀ values of 3.5 nM and 4.1 nM, respectively. It prevents ACC subunit dimerization and inhibits fatty acid synthesis. The compound shows allosteric inhibition mechanism. In cancer cell lines, ND-646 disrupts lipid metabolism and reduces cell proliferation. Detailed in vitro data are available in the primary literature. The compound is a valuable tool for studying lipid metabolism in cancer. |
| ln Vivo |
An established twice-daily (BID) oral treatment of nude athymic mice under A549 was formulated at a dose of 25 mg/kg ND-646 25 mg/kg ND-646 BID or 50 mg/kg ND-646 QD once daily (QD) for 31 days in order to investigate the effects of chronic ND-646 treatment on NSCLC tumor growth and determine twice-daily efficacy. Tumor development was not inhibited by ND-646 at 25 mg/kg QD. On the other hand, subcutaneous A549 tumor development was considerably reduced by ND-646 given at 25 mg/kg BID or 50 mg/kg QD. ND-646 was well tolerated during the course of treatment, and after chronic ND-646, no appreciable tumor growth occurred. Loss of weight, a sign that the maximum tolerated dose (MTD) has not been met. An hour following the last dosage, mice were killed, and their tissues were ready for western blot or immunohistochemistry (IHC) analysis. After one hour, P-ACC was not visible in any of the tumors treated with any of the ND-646 doses, indicating effective ND-646 tumor staining and immediate ACC suppression. Be aware that only at the doses of ND-646 (25 mg/kg BID and 50 mg/kg QD) that significantly inhibited tumor development was a significant increase in P-EIF2αS51 expression seen in tumor ducts [1].
In vivo, ND-646 is orally bioavailable. Long-term treatment in xenograft and genetically engineered mouse models of non-small cell lung cancer (NSCLC) shows inhibition of tumor growth. The compound suppresses fatty acid synthesis in vivo. It has been evaluated both as a single agent and in combination with standard chemotherapeutics like carboplatin. ND-646 is a valuable tool for studying ACC function in cancer metabolism. |
| Enzyme Assay |
In vitro ACC activity assays for ND-646 typically use recombinant ACC1 or ACC2 enzyme and radiolabeled or spectrophotometric substrates. The compound is dissolved in DMSO and diluted in assay buffer (50 mM HEPES, pH 7.5, 10 mM citrate, 10 mM MgCl₂, 2 mM ATP, 5 mM KHCO₃). Reactions are initiated by adding acetyl-CoA and incubated at 37°C for 10-30 minutes. Malonyl-CoA production is detected by measuring [¹⁴C]malonyl-CoA or by using a coupled enzyme assay. IC₅₀ values are calculated from dose-response curves. Allosteric inhibition is confirmed by kinetic analysis. Controls include DMSO vehicle and known ACC inhibitors.
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| Cell Assay |
For cell-based assays, NSCLC cell lines (e.g., A549, H1299) are cultured in DMEM with 10% FBS. Cells are seeded in 96-well plates and treated with ND-646 at various concentrations (0.001-10 μM) for 24-72 hours. Fatty acid synthesis is measured by [¹⁴C]acetate or [³H]palmitate incorporation. Lipid content is assessed by Oil Red O staining or mass spectrometry. Cell viability is assessed by MTT or CellTiter-Glo. Cell proliferation is assessed by colony formation assays. All treatments include vehicle controls and are performed in triplicate.
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| Animal Protocol |
In vivo, ND-646 is typically administered orally to rodents. The compound is formulated in a suitable vehicle such as 0.5% methylcellulose or PEG-based solutions. For NSCLC models, mice bearing xenograft or genetically engineered tumors are dosed at various regimens (e.g., 10-50 mg/kg). Endpoints include tumor volume measurement, survival analysis, and biomarker assessment (fatty acid synthesis, ACC activity in tumor tissues). Blood and tissue samples are collected for pharmacokinetic and pharmacodynamic analysis. All procedures follow institutional animal care guidelines.
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| ADME/Pharmacokinetics |
ND-646 (MW 568.64, C₂₈H₃₂N₄O₇S) is an orally bioavailable ACC inhibitor. It inhibits hACC1 and hACC2 with IC₅₀ values of 3.5 nM and 4.1 nM, respectively. The compound is soluble in DMSO. Detailed pharmacokinetic parameters (bioavailability, half-life, Cmax, AUC) are available from preclinical studies. The compound is typically stored at -20°C. It is designed for research applications in cancer metabolism.
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| Toxicity/Toxicokinetics |
Toxicology data for ND-646 are limited in publicly available sources. As a metabolic enzyme inhibitor, potential effects on normal fatty acid metabolism should be considered. The compound is for research use only and not intended for human therapeutic applications. Standard safety pharmacology and toxicology studies would be required for therapeutic development. The compound should be handled with standard laboratory safety precautions.
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| References | |
| Additional Infomation |
ND-646 is a research-grade ACC inhibitor for studying lipid metabolism in cancer. Its primary applications include cancer research, metabolism, and drug discovery. The compound is not approved for clinical use and has not entered clinical trials. It is commercially available from various chemical suppliers for research purposes only. Its mechanism involves allosteric inhibition of ACC1 and ACC2, suppressing de novo fatty acid synthesis and inhibiting tumor growth.
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| Molecular Formula |
C28H32N4O7S
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|---|---|
| Molecular Weight |
568.641285896301
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| Exact Mass |
568.199
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| Elemental Analysis |
C, 59.14; H, 5.67; N, 9.85; O, 19.69; S, 5.64
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| CAS # |
1434639-57-2
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| Related CAS # |
1434639-57-2;
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| PubChem CID |
71570560
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| Appearance |
White to off-white solid powder
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| LogP |
2.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
40
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| Complexity |
948
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(SC2=C1C(=O)N(C(=O)N2C[C@@H](C3=CC=CC=C3OC)OC4CCOCC4)C(C)(C)C(=O)N)C5=NC=CO5
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| InChi Key |
HSRWXLIYNCKHRZ-FQEVSTJZSA-N
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| InChi Code |
InChI=1S/C28H32N4O7S/c1-16-21-24(33)32(28(2,3)26(29)34)27(35)31(25(21)40-22(16)23-30-11-14-38-23)15-20(39-17-9-12-37-13-10-17)18-7-5-6-8-19(18)36-4/h5-8,11,14,17,20H,9-10,12-13,15H2,1-4H3,(H2,29,34)/t20-/m0/s1
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| Chemical Name |
(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanamide
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| Synonyms |
ND-646 ND 646 ND646.
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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 |
| 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) |
DMSO : ≥ 100 mg/mL (~175.86 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (5.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7586 mL | 8.7929 mL | 17.5858 mL | |
| 5 mM | 0.3517 mL | 1.7586 mL | 3.5172 mL | |
| 10 mM | 0.1759 mL | 0.8793 mL | 1.7586 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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