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| 25mg |
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| 50mg |
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| 250mg |
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ND-646 is-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53-/- (formerly known as KRAS p53) and Kras;Stk11-/- (formerly known as KRAS Lkb1) mouse models of NSCLC. ND-646 had enhanced efficacy when combined with carboplatin, a common component of chemotherapeutic regimens used to treat human NSCLC.
| 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].
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| 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].
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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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| Molecular Formula |
C28H32N4O7S
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|---|---|
| Molecular Weight |
568.641285896301
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| Exact Mass |
568.1992
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| CAS # |
1434639-57-2
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| Related CAS # |
1434639-57-2;
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| SMILES |
CC(C)(N(C(N(C[C@@H](C1=CC=CC=C1OC)OC2CCOCC2)C3=C4C(C)=C(C5=NC=CO5)S3)=O)C4=O)C(N)=O
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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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| 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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