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Fatostatin A is a novel, potent and cell permeable inhibitor of SREBP (Sterol regulatory element-binding protein) activation with anticancer activity. It acts by directly binding SCAP and blocking its ER-to-Golgi transport with IC50 of 2.5 and 10 μM in mammalian cells. Fatostatin blocks ER exit of SCAP and showed that inhibition is independent of insulin-induced gene proteins, which function to retain the SCAP-SREBP complex in the ER. Fatostatin potently inhibited cell growth, but unexpectedly exogenous lipids failed to rescue proliferation of fatostatin-treated cells. Furthermore, fatostatin inhibited growth of cells lacking SCAP. In summary, fatostatin inhibited SREBP activation, but fatostatin additionally inhibited cell proliferation through both lipid-independent and SCAP-independent mechanisms, possibly by general inhibition of ER-to-Golgi transport. Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of cellular lipid homeostasis and activate expression of genes required for fatty acid, triglyceride, and cholesterol synthesis and uptake. SREBP cleavage activating protein (SCAP) plays an essential role in SREBP activation by mediating endoplasmic reticulum (ER)-to-Golgi transport of SREBP. In the Golgi, membrane-bound SREBPs are cleaved sequentially by the site-1 and site-2 proteases. Recent studies have shown a requirement for the SREBP pathway in the development of fatty liver disease and tumor growth, making SCAP a target for drug development.
| ln Vitro |
Independent of the established IGF1 signal amplifier, fatostatin (125B11) (0.1–1 μM; 3 days) prevents androgen-free ischemia (IC50=0.1 μM). With an IC50 of 2.5 and 10 μM in Cell Helper, fatostatin directly binds SCAP and inhibits its endoplasmic reticulum-to-Golgi transit, inhibiting insulin-sensing adipogenesis in 3T3-L1 cells.
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| ln Vivo |
Fatostatin (125B11) (30 mg/kg; 150 μL; i.p.; once daily for 28 days) decreases nutrition by reducing triglyceride (TG) stores, improves fatty liver disease, and reduces high ob/ob ratios in
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| Cell Assay |
Cell proliferation assay [1]
Cell Types: DU-145 Cell Tested Concentrations: 0.1, 1 μM Incubation Duration: 3 days Experimental Results: Attenuated IGF1-induced growth at an IC50 of 0.1 μM. |
| Animal Protocol |
Animal/Disease Models: Four to five week old homozygous male obese (ob/ob) mice (C57BL/6J)[2]
Doses: 30 mg/kg; Hypertension[2]. 150 μL Route of Administration: intraperitoneal (ip) injection; one time/day for 28 days Experimental Results: Body weight, blood glucose, and hepatic fat accumulation in obese ob/ob mice were prevented even without controlling food intake. |
| References |
[1]. Choi Y, et al. Identification of bioactive molecules by adipogenesis profiling of organic compounds. J Biol Chem. 2003 Feb 28;278(9):7320-4.
[2]. Kamisuki S, et al. A small molecule that blocks fat synthesis by inhibiting the activation of SREBP. Chem Biol. 2009 Aug 28;16(8):882-92. [3]. Li X et al. Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol Cancer Ther. 2014 Apr;13(4):855-66. [4]. Shao W et al. Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner. J Lipid Res. 2016 Aug;57(8):1564-73. [5]. Inoue K et al. Fatostatin, an SREBP inhibitor, prevented RANKL-induced bone loss by suppression of osteoclast differentiation. Biochim Biophys Acta. 2015 Nov;1852(11):2432-41. |
| Molecular Formula |
C18H18N2S.HBR
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|---|---|
| Molecular Weight |
375.32586
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| CAS # |
125256-00-0
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| Related CAS # |
Fatostatin hydrobromide;298197-04-3
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| SMILES |
CC1=CC=C(C2=CSC(C3=CC(CCC)=NC=C3)=N2)C=C1
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| InChi Key |
ZROSUBKIGBSZCG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18N2S/c1-3-4-16-11-15(9-10-19-16)18-20-17(12-21-18)14-7-5-13(2)6-8-14/h5-12H,3-4H2,1-2H3
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| Chemical Name |
2-(2-propylpyridin-4-yl)-4-(p-tolyl)thiazole
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| Synonyms |
125B11; Fatostatin A; 125B-11
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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 : ≥ 27 mg/mL (~91.71 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.49 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. Solubility in Formulation 2: 2.5 mg/mL (8.49 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 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: 2.5 mg/mL (8.49 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6643 mL | 13.3216 mL | 26.6432 mL | |
| 5 mM | 0.5329 mL | 2.6643 mL | 5.3286 mL | |
| 10 mM | 0.2664 mL | 1.3322 mL | 2.6643 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.
Fatostatin inhibits SREBP activation.J Lipid Res. 2016 Aug;57(8):1564-73.
Lipid does not rescue fatostatin inhibition of cell growth.J Lipid Res. 2016 Aug;57(8):1564-73. |
Fatostatin blocks ER-to-Golgi transport of SCAP.J Lipid Res. 2016 Aug;57(8):1564-73.
Fatostatin inhibits growth inSCAPknockout cells.J Lipid Res. 2016 Aug;57(8):1564-73. |
Fatostatin inhibition of SREBP does not require INSIG.
Fatostatin inhibits secretion of VSVG.J Lipid Res. 2016 Aug;57(8):1564-73. |
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