PF-06424439 |
| Catalog No.GC18959 |
PF-06424439 is a highly efficient and orally bioavailable selective diacylglycerol acyltransferase 2 (DGAT2) small molecule inhibitor with an IC50 value of 14nM.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1469284-79-4
Sample solution is provided at 25 µL, 10mM.
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PF-06424439 is a highly efficient and orally bioavailable selective diacylglycerol acyltransferase 2 (DGAT2) small molecule inhibitor with an IC50 value of 14nM[1]. DGAT2 is the rate-limiting enzyme in the triacylglycerol (TAG) pathway. PF-06424439 can inhibit TAG synthesis and reduce liver and circulating lipid levels[2,3].
In vitro, after treating MCF7 cells with PF-06424439 at concentrations of 1, 10, 50, 100 and 200μM for 24, 48, 72 and 96 hours respectively, it was found that PF-06424439 inhibited cell growth in a dose and time dependent manner. Treatment with PF-06424439 (10μM) for 72 hours reduced the expressions of key enzymes involved in lipid metabolism, namely 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), fatty acid synthase (FASN), and DGAT2 and inhibited lipid droplet formation[2,4].
In vivo, PF-06424439 was administered intragastally to rats on a high-sucrose and low-fat diet at concentrations of (0.01, 0.03, 0.1, 0.3, 1, 3, 10mg/kg). Two hours later, it was found that the plasma TG level decreased in a dose-dependent manner, significantly inhibiting TG synthesis[1].
References:
[1]Futatsugi K, Kung DW, Orr ST, Cabral S, Hepworth D, Aspnes G, Bader S, Bian J, Boehm M, Carpino PA, Coffey SB, Dowling MS, Herr M, Jiao W, Lavergne SY, Li Q, Clark RW, Erion DM, Kou K, Lee K, Pabst BA, Perez SM, Purkal J, Jorgensen CC, Goosen TC, Gosset JR, Niosi M, Pettersen JC, Pfefferkorn JA, Ahn K, Goodwin B. Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). J Med Chem. 2015 Sep 24;58(18):7173-85.
[2] Nisticò C, Pagliari F, Chiarella E, Fernandes Guerreiro J, Marafioti MG, Aversa I, Genard G, Hanley R, Garcia-Calderón D, Bond HM, Mesuraca M, Tirinato L, Spadea MF, Seco JC. Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation. Int J Mol Sci. 2021 Sep 18;22(18):10102.
[3]Takemoto K, Fukasaka Y, Yoshimoto R, Nambu H, Yukioka H. Diacylglycerol acyltransferase 1/2 inhibition induces dysregulation of fatty acid metabolism and leads to intestinal barrier failure and diarrhea in mice. Physiol Rep. 2020 Aug;8(15):e14542.
[4]Pabst B, Futatsugi K, Li Q, Ahn K. Mechanistic Characterization of Long Residence Time Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2). Biochemistry. 2018 Dec 26;57(51):6997-7010.
| Cell experiment [1]: | |
Cell lines | MCF7 cells |
Preparation Method | Cell viability was determined using PrestoBlue Reagent 10×. MCF7 cells were seeded at 4.7×103 cells/well in 96-well black polystyrene microplates and incubated overnight at 37°C to allow for cell attachment. The next day, cells were treated with 1, 10, 50, 100, 200μM of PF-06424439 for 24, 48, 72 and 96h. At each time point, cells were washed with HBSS and incubated in the dark at 37°C with 10μL of Presto Blue Cell Viability Reagent diluted in 90μL of fresh complete medium for 90min. Cell viability was measured at 560nm and 590nm using a CLARIOstar® microplate reader. Anti-proliferative activity of PF-06424439 was calculated as 50% inhibitory concentration (IC50) at 72h and curve-fitting was performed by non-linear regression analysis by using GraphPad Prism 9 software. |
Reaction Conditions | 1, 10, 50, 100, 200μM; 24, 48, 72 , 96h |
Applications | PF-06424439 can reduce the expression of key enzymes involved in lipid metabolism, namely 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMGCR), fatty acid synthase (FASN), and DGAT2, and inhibit lipid droplet formation. |
| Animal experiment [2]: | |
Animal models | Male Sprague–Dawley rats |
Preparation Method | Male Sprague–Dawley rats were fed a high-sucrose, low-fat diet 2 days prior to the study. On the day of the study, animals were fasted for 4h prior to treatment. Immediately before dosing, blood was drawn from the lateral tail vein into a dipotassium ethylenediaminetetraacetic acid-containing tube. Following centrifugation, the plasma was transferred to a fresh tube for the determination of TG levels using a Roche Hitachi Chemistry analyzer. Animals were dosed with 0.01, 0.03, 0.1, 0.3, 1, 3, 10mg/kg PF-06424439 as a solution in 0.5% w/v methylcellulose (10mL/kg dosing volume). Vehicle-treated animals received 0.5% methylcellulose alone. After a further 2h, blood was drawn and TG determined as described above. |
Dosage form | 0.01, 0.03, 0.1, 0.3, 1, 3, 10mg/kg; p.o. |
Applications | PF-06424439 reduces the plasma TG level in a dose-dependent manner and significantly inhibits TG synthesis. |
References: | |
| Cas No. | 1469284-79-4 | SDF | |
| Chemical Name | [(3R)-1-[2-[1-(4-chloro-1H-pyrazol-1-yl)cyclopropyl]-3H-imidazo[4,5-b]pyridin-5-yl]-3-piperidinyl]-1-pyrrolidinyl-methanone, monomethanesulfonate | ||
| Canonical SMILES | O=C(N1CCCC1)[C@@H]2CCCN(C3=NC(N=C(C4(CC4)N5N=CC(Cl)=C5)N6)=C6C=C3)C2.OS(C)(=O)=O | ||
| Formula | C22H26ClN7O.CH3SO3H | M.Wt | 536 |
| Solubility | DMSO : 250 mg/mL (466.37 mM; Need ultrasonic); H2O : 50 mg/mL (93.27 mM; Need ultrasonic) | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 1.8657 mL | 9.3284 mL | 18.6567 mL |
| 5 mM | 0.3731 mL | 1.8657 mL | 3.7313 mL |
| 10 mM | 0.1866 mL | 0.9328 mL | 1.8657 mL |
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Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 24 reference(s) in Google Scholar.)
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