ND-646
(Synonyms: ACC抑制剂(ND-646)) 目录号 : GC32706
An ACC inhibitor
Cas No.:1434639-57-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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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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ND-646 is an inhibitor of acetyl-CoA carboxylase 1 (ACC1) and ACC2 (IC50s = 3.5 and 4.1 nM, respectively, for the human enzymes).1 It inhibits the production of palmitate and reduces the total fatty acid content in A549 non-small cell lung cancer (NSCLC) cells when used at a concentration of 500 nM. ND-646 (500 nM) induces apoptosis and endoplasmic reticulum (ER) stress in A549 cells. It inhibits fatty acid synthesis and reduces tumor growth in an A549 mouse xenograft model when administered at a dose of 25 mg/kg twice per day.
1.Svensson, R.U., Parker, S.J., Eichner, L.J., et al.Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical modelsNat. Med.22(10)1108-1119(2016)
| Cas No. | 1434639-57-2 | SDF | |
| 别名 | ACC抑制剂(ND-646) | ||
| 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 | ||
| 分子式 | C28H32N4O7S | 分子量 | 568.64 |
| 溶解度 | DMSO : ≥ 100 mg/mL (175.86 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
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.PMID:27643638DOI:10.1038/nm.4181.
Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-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-/- (also known as KRAS p53) and Kras;Stk11-/- (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.
An airway organoid-based screen identifies a role for the HIF1α-glycolysis axis in SARS-CoV-2 infection
Cell Rep 2021 Nov 9;37(6):109920.PMID:34731648DOI:10.1016/j.celrep.2021.109920.
It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (HIF1α), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.
Synthesis and anti-cancer activity of ND-646 and its derivatives as acetyl-CoA carboxylase 1 inhibitors
Eur J Pharm Sci 2019 Sep 1;137:105010.PMID:31325544DOI:10.1016/j.ejps.2019.105010.
Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646, synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC50 values 3-10 nM. Among them, compounds A2, A7 and A9 displayed strong cancer inhibitory activity with IC50 values 9-17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC.
Repurposing a tricyclic antidepressant in tumor and metabolism disease treatment through fatty acid uptake inhibition
J Exp Med 2023 Mar 6;220(3):e20221316.PMID:PMC9757841DOI:10.1084/jem.20221316.
Fatty acid uptake is essential for cell physiological function, but detailed mechanisms remain unclear. Here, we generated an acetyl-CoA carboxylases (ACC1/2) double-knockout cell line, which lacked fatty acid biosynthesis and survived on serum fatty acids and was used to screen for fatty acid uptake inhibitors. We identified a Food and Drug Administration-approved tricyclic antidepressant, nortriptyline, that potently blocked fatty acid uptake both in vitro and in vivo. We also characterized underlying mechanisms whereby nortriptyline provoked lysosomes to release protons and induce cell acidification to suppress macropinocytosis, which accounted for fatty acid endocytosis. Furthermore, nortriptyline alone or in combination with ND-646, a selective ACC1/2 inhibitor, significantly repressed tumor growth, lipogenesis, and hepatic steatosis in mice. Therefore, we show that cells actively take up fatty acids through macropinocytosis, and we provide a potential strategy suppressing tumor growth, lipogenesis, and hepatic steatosis through controlling the cellular level of fatty acids.