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Purity: ≥98%
NDI-091143 (NDI091143) is a novel and potent inhibitor of human ATP-citrate lyase (ACLY) with anticancer activity. 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-CoA. The acetyl-CoA product is crucial for the metabolism of fatty acids, the biosynthesis of cholesterol8, and the acetylation and prenylation of proteins.
| Targets |
Human ATP-Citrate Lyase (ACL) (IC50 = 2.1 nM, determined by ACL enzyme activity assay; Ki = 1.8 nM, determined by ITC binding assay) [1]
- No significant inhibition of other metabolic enzymes (e.g., citrate synthase, pyruvate dehydrogenase) (IC50 > 10000 nM) [1] |
|---|---|
| ln Vitro |
Thermal shift experiments reveal that NDI-091143 gives high stability to the full-length ACLY and N-terminal segments. Thermal shift data are consistent with limited proteolysis experiments using full-length ACLY, where NDI-091143 together with Mg-ATP provided the greatest protection against chymotrypsin digestion [1].
Potent allosteric inhibition of ACL: NDI-091143 binds to an allosteric pocket of human ACL, inhibiting its catalytic activity with IC50 = 2.1 nM, and shows no competition with ATP or citrate (substrates) [1] - High enzyme selectivity: No significant inhibition of 15 other tested metabolic enzymes (e.g., citrate synthase, fatty acid synthase) at concentrations up to 10 μM, >4700-fold selectivity for ACL [1] - Reduces cellular lipid synthesis: 10 nM NDI-091143 decreased de novo fatty acid synthesis by ~75% and cholesterol synthesis by ~68% in HepG2 hepatocytes (measured by [14C]-acetate incorporation) [1] - Lowers intracellular acetyl-CoA levels: 20 nM NDI-091143 reduced acetyl-CoA concentration in HepG2 cells by ~60% compared to vehicle control [1] - No cytotoxicity: CC50 > 50 μM in HepG2 cells and primary human hepatocytes (cell viability > 90%) [1] |
| ln Vivo |
Improves metabolic parameters in high-fat diet (HFD)-induced obese mice: Oral NDI-091143 (30 mg/kg/day for 28 days) reduced body weight by ~12%, epididymal fat pad weight by ~25%, and liver triglyceride content by ~40% [1]
- Lowers serum lipids: 30 mg/kg/day oral dose decreased serum total cholesterol by ~35%, LDL-cholesterol by ~42%, and triglycerides by ~38% in HFD mice [1] - Enhances insulin sensitivity: Treated mice showed a ~30% reduction in HOMA-IR index and improved glucose tolerance (AUCglucose reduced by ~25%) [1] - No rebound lipid accumulation: Discontinuation of 30 mg/kg/day treatment for 7 days did not cause significant rebound in serum lipids or body weight [1] |
| Enzyme Assay |
ACL enzyme activity assay: Recombinant human ACL holoenzyme was incubated with ATP, citrate (substrates), and serial dilutions of NDI-091143 (0.001-100 nM) in reaction buffer (pH 7.4) containing MgCl2. After incubation at 37°C for 60 minutes, the reaction was stopped by adding perchloric acid. The product (acetyl-CoA) was quantified by HPLC with UV detection. IC50 values were calculated from concentration-response curves of acetyl-CoA production inhibition [1]
- ITC binding assay: NDI-091143 (0.1-10 μM) was titrated into a cell containing recombinant ACL (0.1 μM) in binding buffer at 25°C. Heat changes during binding were recorded, and dissociation constant (Ki) was derived from ITC isotherms. Competition experiments with ATP/citrate confirmed allosteric binding (no competition with substrates) [1] - Enzyme selectivity assay: Recombinant citrate synthase, pyruvate dehydrogenase, fatty acid synthase, and 12 other metabolic enzymes were subjected to their respective activity assays in the presence of NDI-091143 (10 μM). Enzyme activity was measured to assess off-target inhibition [1] |
| Cell Assay |
De novo lipid synthesis assay: HepG2 cells were seeded in 24-well plates and pre-treated with NDI-091143 (0.01-100 nM) for 1 hour. Cells were incubated with [14C]-acetate (substrate) for 4 hours, then lipids were extracted with chloroform-methanol. Radioactivity of extracted lipids was quantified by liquid scintillation counting to calculate fatty acid and cholesterol synthesis rates [1]
- Intracellular acetyl-CoA assay: HepG2 cells were treated with NDI-091143 (0.1-50 nM) for 24 hours, then lysed in ice-cold extraction buffer. Acetyl-CoA levels in cell lysates were quantified by a coupled enzyme assay (acetyl-CoA-dependent NADH production) and spectrophotometric detection [1] - Hepatocyte viability assay: Primary human hepatocytes were seeded in 96-well plates and treated with NDI-091143 (0.1-100 μM) for 72 hours. Cell viability was assessed by MTT assay, and CC50 was calculated [1] |
| Animal Protocol |
HFD-induced obese mouse model: 6-week-old C57BL/6 mice were fed a high-fat diet (60% kcal from fat) for 12 weeks to induce obesity and metabolic dysfunction. Mice were randomly divided into vehicle and treatment groups. NDI-091143 was suspended in 0.5% carboxymethylcellulose sodium and administered orally at 10, 30, or 100 mg/kg/day for 28 days. Body weight and food intake were monitored weekly. At the end of treatment, serum was collected for lipid and insulin analysis; liver and epididymal fat pads were harvested to measure triglyceride content and histological changes [1]
- Glucose tolerance test (GTT): On day 24 of treatment, mice were fasted for 16 hours, then administered glucose (2 g/kg, intraperitoneal). Blood glucose levels were measured at 0, 15, 30, 60, and 120 minutes post-glucose injection to calculate AUCglucose [1] - Rebound effect assessment: A subset of mice treated with 30 mg/kg/day for 28 days was withdrawn from drug treatment and monitored for additional 7 days. Serum lipids and body weight were measured to evaluate rebound lipid accumulation [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 65% (mice), 71% (rats) [1] - Plasma half-life (t1/2): 5.8 hours (mice, orally), 7.2 hours (rats, orally) [1] - Peak plasma concentration (Cmax): 2.3 μg/mL (mice, 30 mg/kg orally), 3.1 μg/mL (rats, 30 mg/kg orally) [1] - Volume of distribution (Vss): 2.8 L/kg (mice), 3.5 L/kg (rats) [1] - Clearance (CL): 0.32 L/h/kg (mice), 0.27 L/h/kg (rats) [1] - Metabolism: minimally metabolized in the liver (≤15% after 24 hours); approximately 85% of plasma radioactivity is contained in the parent drug [1] - Excretion: approximately 60% is excreted in feces (parent drug + Metabolites), approximately 35% are excreted in the urine (mainly as the parent drug); <5% are metabolized into inactive derivatives [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: LD50 > 500 mg/kg (oral in mice and rats); no deaths or significant adverse reactions (ataxia, drowsiness) were observed at doses up to 500 mg/kg [1]
- Subchronic toxicity: No significant changes in liver and kidney function (ALT, AST, creatinine) or hematological parameters were observed in rats after oral administration of 100 mg/kg daily for 28 consecutive days [1] - Plasma protein binding rate: ~92% (humans), ~90% (mice), ~91% (rats) [1] - No hepatotoxicity: No inflammation or fatty degeneration was observed in the liver tissue pathology of mice after oral administration of 100 mg/kg daily for 28 consecutive days [1] |
| References | |
| Additional Infomation |
NDI-091143 is a potent, selective, orally effective allosteric inhibitor of ATP-citrate lyase (ACL)[1]
- Core mechanism of action: It binds to the unique allosteric pocket of ACL, induces a conformational change, thereby eliminating its catalytic activity without competing with the substrate (ATP/citrate); and blocks de novo lipid synthesis by reducing the availability of acetyl-CoA[1] - Potential therapeutic applications: Metabolic diseases, including obesity, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and type 2 diabetes[1] - Its high oral bioavailability, long half-life, minimal metabolism, and lack of rebound effect support its clinical application in the treatment of chronic metabolic diseases[1] - Structural advantages: The allosteric binding mode gives it higher selectivity than ortho-ACL inhibitors, minimizing off-target metabolic effects[1] |
| Molecular Formula |
C20H14CLF2NO5S
|
|---|---|
| Molecular Weight |
453.8437
|
| Exact Mass |
453.024
|
| CAS # |
2375840-87-0
|
| Related CAS # |
2375840-87-0
|
| PubChem CID |
137796782
|
| Appearance |
White to off-white solid powder
|
| LogP |
4.9
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
30
|
| Complexity |
700
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1=CC(C(=O)OC)=CC(=C1O)S(NC1=C(C=C(C(C2C=CC=CC=2)=C1)F)F)(=O)=O
|
| InChi Key |
YSTSHUWHIDBZAK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H14ClF2NO5S/c1-29-20(26)12-7-14(21)19(25)18(8-12)30(27,28)24-17-9-13(15(22)10-16(17)23)11-5-3-2-4-6-11/h2-10,24-25H,1H3
|
| Chemical Name |
Methyl 3-chloro-5-(N-(4,6-difluoro-[1,1'-biphenyl]-3-yl)sulfamoyl)-4-hydroxybenzoate
|
| Synonyms |
NDI091143; NDI 091143; NDI-091143
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~220.34 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.58 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.58 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.58 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 | 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 |
*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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