NDI-091143
目录号 : GC38932
An ACL inhibitor
Cas No.:2375840-87-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
NDI-091143 is an allosteric inhibitor of ATP citrate lyase (ACL; Ki = 7 nM).1 It inhibits the production of ADP in a cell-free assay and oxaloacetate production in an enzyme-coupled assay (IC50s = 2.1 and 4.8 nM, respectively).
1.Wei, J., Leit, S., Kuai, J., et al.An allosteric mechanism for potent inhibition of human ATP-citrate lyaseNature568(7753)566-570(2019)
| Cas No. | 2375840-87-0 | SDF | |
| Canonical SMILES | O=C(OC)C1=CC(S(=O)(NC2=CC(C3=CC=CC=C3)=C(F)C=C2F)=O)=C(O)C(Cl)=C1 | ||
| 分子式 | C20H14ClF2NO5S | 分子量 | 453.84 |
| 溶解度 | DMSO: 125 mg/mL (275.43 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 | 2.2034 mL | 11.0171 mL | 22.0342 mL |
| 5 mM | 0.4407 mL | 2.2034 mL | 4.4068 mL |
| 10 mM | 0.2203 mL | 1.1017 mL | 2.2034 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。
Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor
J Chem Inf Model 2022 Jun 27;62(12):3123-3132.PMID:35679529DOI:10.1021/acs.jcim.2c00345.
ATP citrate lyase (ACLY) is an important metabolic enzyme involved in the synthesis of fatty acid and cholesterol. The inhibition of ACLY is considered as a promising therapeutic strategy for various metabolic diseases and numerous malignancies. In this study, a novel macrocyclic compound 2 has been identified as a potent ACLY inhibitor with the "ring closing" strategy for conformational restriction based on NDI-091143. It showed potent ACLY inhibitory activity and binding affinity comparable to the positive control. Furthermore, compared with the positive control (T1/2 = 3.36 min), the metabolic stability of 2 in HLMs (T1/2 = 531.22 min) was significantly improved. All of these results characterized 2 as a promising lead compound worthy of further study.
ACLY inhibitors induce apoptosis and potentiate cytotoxic effects of sorafenib in thyroid cancer cells
Endocrine 2022 Oct;78(1):85-94.PMID:35761130DOI:10.1007/s12020-022-03124-6.
Purpose: ATP-citrate lyase (ACLY) is a critical enzyme at the intersection of glucose and lipid metabolism. ACLY is often upregulated or activated in cancer cells to accelerate lipid synthesis and promote tumor progression. In this study, we aimed to explore the possibility of utilizing ACLY inhibition as a new strategy in the treatment of thyroid cancer. Methods: Bioinformatics analysis of the public datasets was performed. Thyroid cancer cells were treated with two different ACLY inhibitors, SB-204990 and NDI-091143. Results: Bioinformatics analysis revealed that ACLY expression was increased in anaplastic thyroid cancer. In thyroid cancer cell lines FTC-133 and 8505C, ACLY inhibitors suppressed monolayer cell growth and clonogenic ability in a dose-dependent and time-dependent manner. Flow cytometry analysis showed that ACLY inhibitors increased the proportion of sub-G1 cells in the cell cycle and the number of annexin V-positive cells. Immunoblotting confirmed caspase-3 activation and PARP1 cleavage following treatment with ACLY inhibitors. Compromised cell viability could be partially rescued by co-treatment with the pan-caspase inhibitor Z-VAD-FMK. Additionally, we showed that ACLY inhibitors impeded three-dimensional growth and cell invasion in thyroid cancer cells. Isobolograms and combination index analysis indicated that ACLY inhibitors synergistically potentiated the cytotoxicity rendered by sorafenib. Conclusions: Targeting ACLY holds the potential for being a novel therapeutic strategy for thyroid cancer.
ATP-citrate lyase inhibitor improves ectopic lipid accumulation in the kidney in a db/db mouse model
Front Endocrinol (Lausanne) 2022 Dec 8;13:914865.PMID:36568100DOI:10.3389/fendo.2022.914865.
Aim: We evaluated a novel treatment for obesity-related renal, an ATP-citrate lyase (ACL) inhibitor, to attenuate ectopic lipid accumulation (ELA) in the kidney and the ensuing inflammation. Materials and methods: An ACL inhibitor was administered intragastrically to 12-week-old db/db mice for 30 days. The appearance of ELA was observed by staining kidney sections with Oil Red O, and the differences in tissue lipid metabolites were assessed by mass spectrometry. The anti-obesity and renoprotection effects of ACL inhibitors were observed by histological examination and multiple biochemical assays. Results: Using the AutoDock Vina application, we determined that among the four known ACL inhibitors (SB-204990, ETC-1002, NDI-091143, and BMS-303141), BMS-303141 had the highest affinity for ACL and reduced ACL expression in the kidneys of db/db mice. We reported that BMS-303141 administration could decrease the levels of serum lipid and renal lipogenic enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), HMG-CoA reductase (HMGCR), and diminish renal ELA in db/db mice. In addition, we found that reducing ELA improved renal injuries, inflammation, and tubulointerstitial fibrosis. Conclusion: ACL inhibitor BMS-303141 protects against obesity-related renal injuries.
Discovery of Allosteric Inhibition of Human ATP-Citrate Lyase
Trends Pharmacol Sci 2019 Jun;40(6):364-366.PMID:31072639DOI:10.1016/j.tips.2019.04.008.
ATP-citrate lyase (ACLY) is an enzyme that links glycolysis to lipid metabolism. To date only partial X-ray structures of ACLY have been solved, thus limiting the design of novel inhibitors. Wei and colleagues (published online in Nature April 3, 2019) now report the full structure of human ACLY in complex with NDI-091143, revealing an appealing allosteric inhibition mechanism for this compound.
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
Nature 2019 Apr;568(7753):566-570.PMID:30944472DOI:10.1038/s41586-019-1094-6.
ATP-citrate lyase (ACLY) is a central metabolic enzyme and catalyses the ATP-dependent conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA1-5. The acetyl-CoA product is crucial for the metabolism of fatty acids6,7, the biosynthesis of cholesterol8, and the acetylation and prenylation of proteins9,10. There has been considerable interest in ACLY as a target for anti-cancer drugs, because many cancer cells depend on its activity for proliferation2,5,11. ACLY is also a target against dyslipidaemia and hepatic steatosis, with a compound currently in phase 3 clinical trials4,5. Many inhibitors of ACLY have been reported, but most of them have weak activity5. Here we report the development of a series of low nanomolar, small-molecule inhibitors of human ACLY. We have also determined the structure of the full-length human ACLY homo-tetramer in complex with one of these inhibitors (NDI-091143) by cryo-electron microscopy, which reveals an unexpected mechanism of inhibition. The compound is located in an allosteric, mostly hydrophobic cavity next to the citrate-binding site, and requires extensive conformational changes in the enzyme that indirectly disrupt citrate binding. The observed binding mode is supported by and explains the structure-activity relationships of these compounds. This allosteric site greatly enhances the 'druggability' of ACLY and represents an attractive target for the development of new ACLY inhibitors.