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Purity: ≥98%
MX1013 (Z-VD-fmk) is a novel, a potent and irreversible dipeptide pan-caspase inhibitor which inhibits with IC50 values ranging from 5 to 20 nm that inhibits caspases 1, 3, 6, 7, 8, and 9. Caspases are thought to be important targets for the development of cytoprotective drugs because they play a significant role in apoptosis. Cathepsin B, calpain I, and factor Xa are examples of noncaspase proteases that MX1013 does not effectively inhibit (IC50 values >10 microm). MX1013 is more effective than tetrapeptide- and tripeptide-based caspase inhibitors in a number of cell culture models of apoptosis, such as caspase 3 processing, PARP cleavage, and DNA fragmentation, and it inhibited apoptosis at concentrations as low as 0.5 microm. Compared to caspase inhibitors based on tripeptides like Z-VAD-fmk, MX1013 is more soluble in water. In the anti-Fas mouse-liver apoptosis model, a commonly used liver failure model, MX1013 prevented liver damage and the lethality brought on by Fas death receptor activation at a dose of 1 mg kg-1 intravenously. In a model of brain ischemia/reperfusion injury, MX1013 reduced cortical damage by about 50% at a dose of 20 mg kg-1 (i.v. bolus followed by i.v. infusion for 6 or 12 h). At a dose of 20 mg kg-1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction. These studies lead to the conclusion that MX1013, a dipeptide pan-caspase inhibitor, has an effective combination of in vitro and in vivo characteristics. It is systemically active in three animal models of apoptosis, including brain ischemia, and has the capacity to defend cells from a variety of apoptotic insults.
| Targets |
Caspase
MX1013 has an IC50 range of 5 to 20 nm and inhibits caspases 1, 3, 6, 7, 8, and 9. Cathepsin B, calpain I, and factor Xa are examples of noncaspase proteases that are poorly inhibited by MX1013 (IC50 values >10 μm)[1]. The maturation of caspase 3 through proteolysis, the cleavage of PARP by caspase, and the fragmentation of genomic DNA are the three primary indicators of apoptosis that MX1013 inhibits[1]. |
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| ln Vitro |
MX1013 has an IC50 range of 5 to 20 nm and inhibits caspases 1, 3, 6, 7, 8, and 9. Cathepsin B, calpain I, and factor Xa are examples of noncaspase proteases that are poorly inhibited by MX1013 (IC50 values >10 μm)[1].
The maturation of caspase 3 through proteolysis, the cleavage of PARP by caspase, and the fragmentation of genomic DNA are the three primary indicators of apoptosis that MX1013 inhibits[1]. In HeLa cells treated with TNF-α and cycloheximide, MX1013 showed cytoprotective activity at concentrations as low as 0.5 μM, outperforming tripeptide and tetrapeptide caspase inhibitors. In Jurkat cells treated with anti-Fas antibody, MX1013 at 0.5 μM inhibited caspase-3 processing, PARP cleavage, and DNA fragmentation. In Jurkat cells treated with doxorubicin, MX1013 at 10 μM blocked membrane blebbing, a morphological marker of apoptosis. [1] |
| ln Vivo |
MX1013 is an effective antiapoptotic agent in vivo. MX1013 can shield animals from the deadly effects of local tissue apoptosis in addition to inhibiting it[1].
In an anti-Fas-induced mouse liver apoptosis model, MX1013 administered intravenously at 1 mg/kg prevented lethality and reduced serum levels of liver enzymes SGOT and SGPT. In a rat transient focal cerebral ischemia model, MX1013 (20 mg/kg bolus + 5 mg/kg/h infusion for 6 or 12 h) reduced cortical infarct volume by approximately 46–57%. In a rat myocardial infarction model, MX1013 (20 mg/kg bolus + 5 mg/kg/h infusion for 12 h) reduced infarct size by 52%. [1] |
| Enzyme Assay |
The inhibitory activity of MX1013 against recombinant human caspases was determined using a fluorometric microplate assay. Caspase enzyme was incubated with the fluorogenic substrate Ac-DEVD-AMC in buffer containing HEPES or PIPES, NaCl, sucrose, EDTA, CHAPS, and DTT. Substrate cleavage was measured using fluorescence at excitation 355 nm and emission 460 nm.
Inhibition of non-caspase proteases (cathepsin B, calpain I, cathepsin D, renin, Factor Xa, thrombin) was assessed using corresponding fluorogenic substrates under recommended assay conditions. [1] |
| Cell Assay |
HeLa cells were preincubated with MX1013 for 2 h, then treated with TNF-α and cycloheximide for 18–24 h. Cell viability was assessed by phase-contrast microscopy or calcein AM uptake.
Jurkat cells were preincubated with MX1013 for 2 h, then treated with anti-Fas antibody for 4 h. Cells were lysed and analyzed by Western blot for caspase-3 processing and PARP cleavage. Jurkat cells were treated with doxorubicin in the presence or absence of MX1013 and observed for membrane blebbing by microscopy. [1] |
| Animal Protocol |
Female ND4 Swiss Webster mice (16.5-21 g)[1]
0, 0.25, 1, 10 mg/kg (formulated in an aqueous vehicle containing 50 mm Tris-HCl, pH 8.0) Injected i.v. In the mouse liver apoptosis model, female Swiss Webster mice were injected intravenously with anti-Fas antibody, followed 5 min later by MX1013 formulated in 50 mM Tris-HCl (pH 8.0). Survival and serum liver enzymes were monitored. In the rat transient focal brain ischemia model, male Fischer-344 rats underwent middle cerebral artery occlusion for 2.5 h. MX1013 was administered as an intravenous bolus (20 mg/kg) 10 min after occlusion, followed by continuous infusion (5 mg/kg/h) for 6 or 12 h. Infarct volume was assessed by TTC staining. In the rat myocardial infarction model, male Fischer-344 rats underwent left descending coronary artery occlusion for 1 h. MX1013 was given as an intravenous bolus (20 mg/kg) at ischemia onset, followed by infusion (5 mg/kg/h) for 12 h. Infarct size was assessed by TTC staining. [1] |
| ADME/Pharmacokinetics |
MX1013 has better water solubility than tripeptide caspase inhibitors such as Z-VAD(OMe)-fmk. It can be prepared into a 50 mM Tris-HCl aqueous solution (pH 8.0) with a concentration >10 mg/mL for intravenous injection. [1]
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| References | |
| Additional Infomation |
MX1013 is a dipeptide (Val-Asp) coupled with a fluoromethyl ketone group and can act as an irreversible inhibitor of caspase. Compared with longer peptide inhibitors, MX1013 has higher cell permeability, which may be due to its small molecular size and only one charged group. MX1013 is considered a potential therapeutic agent for the treatment of diseases associated with apoptosis, such as liver failure, stroke and myocardial infarction. [1]
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| Molecular Formula |
C18H23N2O6
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|---|---|
| Molecular Weight |
382.38342
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| Exact Mass |
382.154
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| Elemental Analysis |
C, 56.54; H, 6.06; F, 4.97; N, 7.33; O, 25.10
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| CAS # |
582316-00-5
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| Related CAS # |
582316-00-5
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| PubChem CID |
9821317
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| Appearance |
White to off-white solid powder
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| Density |
1.258g/cm3
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| Boiling Point |
639.809ºC at 760 mmHg
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| Flash Point |
340.745ºC
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| Index of Refraction |
1.523
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| LogP |
2.217
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
27
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| Complexity |
534
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC([C@H](NC(OCC1=CC=CC=C1)=O)C(NC(C(CF)=O)CC(O)=O)=O)C
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| InChi Key |
LYBWGROBJJXCJJ-VYIIXAMBSA-N
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| InChi Code |
InChI=1S/C18H23FN2O6/c1-11(2)16(17(25)20-13(8-15(23)24)14(22)9-19)21-18(26)27-10-12-6-4-3-5-7-12/h3-7,11,13,16H,8-10H2,1-2H3,(H,20,25)(H,21,26)(H,23,24)/t13?,16-/m0/s1
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| Chemical Name |
5-fluoro-3-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid
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| Synonyms |
MX1013; MX 1013; MX-1013
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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 |
| 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: ~100 mg/mL (~261.5 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6152 mL | 13.0760 mL | 26.1520 mL | |
| 5 mM | 0.5230 mL | 2.6152 mL | 5.2304 mL | |
| 10 mM | 0.2615 mL | 1.3076 mL | 2.6152 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.
 Effect of caspase inhibitors containing different peptide lengths on TNF-α/CHX-induced apoptosis of HeLa cells.
Comparison of the cytoprotective effects of MX1013 and Z-VAD(OMe)-fmk.Br J Pharmacol. 2003 Sep; 140(2): 402–412. |
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 Effect of MX1013 on recombinant human caspase 3 activity.
The effect of MX1013 on three biochemical markers of apoptosis.Br J Pharmacol. 2003 Sep; 140(2): 402–412. |
 Effects of MX1013 treatment in the cortical infarct volume of animals in a transient MCAO.
Effects of MX1013 treatment in an acute myocardial infarction and reperfusion model in rats.Br J Pharmacol. 2003 Sep; 140(2): 402–412. |
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