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Purity: ≥98%
FIN56 (FIN-56), a specific inducer of ferroptosis, causes the loss of GPX4 activity in cell lysates. Squalene synthase is additionally bound to and activated. It has been discovered that inhibiting the lipid-repair enzyme GPX4 causes ferroptosis. GPX4 was made to degrade faster by FIN56. Independent of the GPX4 degradation, FIN56 also binds to and activates the isoprenoid biosynthesis enzyme squalene synthase. Through a mechanism involving the control of GPX4 protein abundance, FIN56 causes ferroptosis. Overexpression of the GFP-GPX4 fusion protein prevents the cell death caused by FIN56. It binds to and activates squalene synthase, an enzyme involved in the synthesis of cholesterol, to suppress non-steroidogenic metabolites—likely coenzyme Q10—in the mevalonate pathway, increasing sensitivity to FIN56-induced ferroptosis.
| Targets |
Ferroptosis
Regulates ferroptosis via modulation of coenzyme Q10 (CoQ10) biosynthesis and glutathione peroxidase 4 (GPX4) function [1] |
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| ln Vitro |
FIN56 is a specific inducer of ferroptosis. The mechanism involves two distinct pathways: one leads to the degradation of GPX4, which necessitates the enzymatic activity of acetyl-CoA carboxylase, and the other activates squalene synthase, which depletes coenzyme Q10 without relying on the degradation of GPX4[1].
FIN56 (0.1-10 μM) dose-dependently induced ferroptosis in RAS-mutant cancer cell lines: EC50 = 0.8 μM (A375 melanoma), EC50 = 1.2 μM (HT-1080 fibrosarcoma), EC50 = 1.5 μM (SW480 colorectal cancer) after 24 hours [1] - Ferroptosis induced by FIN56 was iron-dependent: pre-treatment with iron chelator deferoxamine (DFO, 100 μM) reduced cell death by 80%; rescued by ferroptosis inhibitor ferrostatin-1 (Fer-1, 1 μM) with 90% cell viability recovery [1] - FIN56 (1 μM, 16 hours) reduced cellular CoQ10 levels by 75% and CoQ10H2 (reduced form) by 82% in A375 cells, disrupting lipid antioxidant defense [1] - FIN56 (1 μM) increased lipid peroxidation by 3.5-fold in HT-1080 cells, as detected by C11-BODIPY fluorescence assay; no significant induction of apoptosis or necrosis (Annexin V/PI staining showed <5% apoptotic cells) [1] - FIN56 -induced ferroptosis was enhanced in GPX4-deficient cells and attenuated in GPX4-overexpressing cells, confirming GPX4 functional dependence [1] |
| ln Vivo |
NA
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| Enzyme Assay |
FIN56 causes the loss of GPX4 activity in cell lysates. FIN56-induced cell death is suppressed by GFP-GPX4 fusion protein overexpression. FIN56 triggers ferroptosis through a mechanism involving the regulation of GPX4 protein abundance.
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| Cell Assay |
In a 10-cm dish, 500,000 HT-1080 cells are seeded. For 16 hours, cells are grown at 37 °C. Cells are cotreated with 100 μM -tocopherol and either a vehicle (DMSO) or a ferroptosis inducer (10 μM erastin, 0.5 μM (1S, 3R)-RSL3, or 5 μM FIN56) on the day of the analysis, and then incubated for 10 h. Next, cells are trypsinized, pelleted, and given a single wash in 400 L of ice-cold PBS containing 1 mM EDTA. Both oxidized and reduced glutathione are quantified in technical triplicates in 120 μL of sample after the cell debris has been pelleted and eliminated. The protein concentration as determined by the Bradford assay is used to normalize the glutathione quantity.
Ferroptosis induction and viability assay: RAS-mutant cancer cells (A375, HT-1080, SW480) were cultured in DMEM medium supplemented with fetal bovine serum. Cells were seeded in 96-well plates, treated with serial concentrations of FIN56 (0.05-20 μM) alone or in combination with DFO (100 μM) or Fer-1 (1 μM). After 24 hours, cell viability was assessed by CCK-8 assay, and EC50 values were calculated from dose-response curves [1] - Lipid peroxidation detection assay: HT-1080 cells were loaded with C11-BODIPY dye (1 μM) for 30 minutes, then treated with FIN56 (1 μM) for 16 hours. Fluorescence intensity (excitation/emission = 488/510 nm for non-oxidized; 580 nm for oxidized) was measured by flow cytometry to quantify lipid peroxidation levels [1] - CoQ10 content quantification assay: A375 cells were treated with FIN56 (1 μM) for 16 hours, then harvested and lysed. CoQ10 and CoQ10H2 were extracted with organic solvent, separated by HPLC, and detected by ultraviolet absorption to calculate relative concentrations [1] - GPX4 dependence assay: GPX4-deficient and GPX4-overexpressing HT-1080 cell lines were generated via CRISPR-Cas9 knockout and plasmid transfection, respectively. Cells were treated with FIN56 (0.5-5 μM) for 24 hours, and cell viability was measured to compare ferroptosis sensitivity [1] |
| Animal Protocol |
NA
NA |
| References |
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| Additional Infomation |
FIN56 is a fluorene compound with the structure N-9H-fluorene-9-methylenehydroxylamine, substituted at positions 2 and 7 with N-cyclohexylsulfonyl groups. It induces ferroptosis by degrading GPX4 and can bind to and activate squalene synthase. FIN56 is both a ferroptosis inducer and an EC 1.11.1.9 (glutathione peroxidase) inhibitor. It belongs to the fluorene, ketooxime, and sulfonamide classes. Functionally, it is related to 9-hydroxyiminofluorene-2,7-disulfonamide.
FIN56 is a small molecule ferroptosis inducer with high selectivity for RAS-mutant cancer cells[1] - Its mechanism of ferroptosis induction involves two key steps: depletion of the lipid antioxidant coenzyme Q10 (by inhibiting the biosynthesis of coenzyme Q10) and inactivation of GPX4 (the major glutathione-dependent lipid peroxidase), leading to uncontrolled lipid peroxidation and cell death[1] - FIN56-induced ferroptosis is strictly iron-dependent and can be specifically reversed by ferroptosis inhibitors (such as Fer-1), but not by apoptosis, necrosis, or autophagy inhibitors[1] - It is a valuable tool compound for studying the metabolic regulation of ferroptosis and exploring RAS-mutant cancer therapies that target iron-dependent cell death[1] |
| Molecular Formula |
C25H31N3O5S2
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| Molecular Weight |
517.6607
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| Exact Mass |
517.17
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| Elemental Analysis |
C, 58.01; H, 6.04; N, 8.12; O, 15.45; S, 12.39
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| CAS # |
1083162-61-1
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| Related CAS # |
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| PubChem CID |
118986699
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| Appearance |
White to off-white solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
35
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| Complexity |
900
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
JLCFMMIWBSZOIS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H31N3O5S2/c29-26-25-23-15-19(34(30,31)27-17-7-3-1-4-8-17)11-13-21(23)22-14-12-20(16-24(22)25)35(32,33)28-18-9-5-2-6-10-18/h11-18,27-29H,1-10H2
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| Chemical Name |
2-N,7-N-dicyclohexyl-9-hydroxyiminofluorene-2,7-disulfonamide
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| Synonyms |
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| 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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.83 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.83 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 (4.83 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 | 1.9318 mL | 9.6588 mL | 19.3177 mL | |
| 5 mM | 0.3864 mL | 1.9318 mL | 3.8635 mL | |
| 10 mM | 0.1932 mL | 0.9659 mL | 1.9318 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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ACC inhibitor prevents GPX4 protein degradationNat Chem Biol.2016 Jul;12(7):497-503 |
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