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Z-LEHD-FMK

Irreversible Caspase-9 inhibitor. CAS# 210345-04-3

Z-LEHD-FMK

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Quality Control of Z-LEHD-FMK

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Chemical structure

Z-LEHD-FMK

3D structure

Chemical Properties of Z-LEHD-FMK

Cas No. 210345-04-3 SDF Download SDF
PubChem ID 10032582 Appearance Powder
Formula C32H43FN6O10 M.Wt 690.72
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble in DMSO
Chemical Name methyl (4S)-5-[[(2S)-1-[[(3S)-5-fluoro-1-methoxy-1,4-dioxopentan-3-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-4-[[(2S)-4-methyl-2-(phenylmethoxycarbonylamino)pentanoyl]amino]-5-oxopentanoate
SMILES CC(C)CC(C(=O)NC(CCC(=O)OC)C(=O)NC(CC1=CN=CN1)C(=O)NC(CC(=O)OC)C(=O)CF)NC(=O)OCC2=CC=CC=C2
Standard InChIKey YXRKBEPGVHOXSV-QORCZRPOSA-N
Standard InChI InChI=1S/C32H43FN6O10/c1-19(2)12-24(39-32(46)49-17-20-8-6-5-7-9-20)30(44)36-22(10-11-27(41)47-3)29(43)38-25(13-21-16-34-18-35-21)31(45)37-23(26(40)15-33)14-28(42)48-4/h5-9,16,18-19,22-25H,10-15,17H2,1-4H3,(H,34,35)(H,36,44)(H,37,45)(H,38,43)(H,39,46)/t22-,23-,24-,25-/m0/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Protocol

Cell experiment [1]:

Cell lines

Human colon cancer, HCT116, human embryonic fibroblastand 293 cell lines

Preparation method

Soluble in DMSO > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

20 μM Z-LEHD-FMK for 30 mins followed by 20ng/ml TRAIL for 4 hours

Applications

Z-LEHD-FMK completely protects HCT116 and 293 cells from TRAIL-induced toxicity. Z-LEHD-FMK also protected human hepatocytes from TRAIL-induced apoptosis. The colony growth of HCT116 is reduced in the presence of TRAIL, and there are significantly more colonies present when the HCT116 cells were incubated in the presence of TRAIL and Z-LEHD-FMK.

Animal experiment [2]:

Animal models

Adult male Wistar albino rats, 250 to 350 g, spinal cord injury model

Dosage form

Intravenous 0.8-mM/kg injection of z-LEHD-fmk.

Preparation method

Dry-form z-LEHD-fmk was dissolved in dimethylsulfoxide prepared with phosphatebuffered saline.

Application

At 24 hours post-injury, the mean apoptotic cell count in trauma-only controls was significantly higher than that in z-LEHD-fmk–treated group. Electron microscopy results also show Z-LEHD-FMK treatment protected neurons, glia, myelin, axons, and intracellular organelles. The specimens treated with z-LEHD-fmk displays significantly fewer apoptotic cells and diminished axonal demyelination.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

1. Ozoren N, Kim K, Burns TF, et al. The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res, 2000, 60(22): 6259-6265.

2. Colak A, Karao lan A, Barut S, et al. Neuroprotection and functional recovery after application of the caspase-9 inhibitor z-LEHD-fmk in a rat model of traumatic spinal cord injury. J Neurosurg Spine, 2005, 2(3): 327-334.

Z-LEHD-FMK Dilution Calculator

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Preparing Stock Solutions of Z-LEHD-FMK

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.4478 mL 7.2388 mL 14.4776 mL 28.9553 mL 36.1941 mL
5 mM 0.2896 mL 1.4478 mL 2.8955 mL 5.7911 mL 7.2388 mL
10 mM 0.1448 mL 0.7239 mL 1.4478 mL 2.8955 mL 3.6194 mL
50 mM 0.029 mL 0.1448 mL 0.2896 mL 0.5791 mL 0.7239 mL
100 mM 0.0145 mL 0.0724 mL 0.1448 mL 0.2896 mL 0.3619 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on Z-LEHD-FMK

Z-LEHD-FMK is a specific and irreversible inhibitor of caspase-9 [1].

Caspase-9 is an initiator caspase and plays an important role in the mitochondrial death pathway. Caspase-9 is activated during programmed cell death and cleaves procaspase-7 and procaspase-3.

Z-LEHD-FMK is a specific and irreversible caspase-9 inhibitor. In HCT116 human colon cancer cell line and 293 human embryonic kidney cell line, Z-LEHD-FMK inhibited apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These results suggested that TRAIL induced death through the mitochondrial pathway in some human cells. In a colony assay, Z-LEHD-FMK inhibited the reduction of colony growth of HCT116 induced by TRAIL. In normal human hepatocytes, Z-LEHD-FMK protected cells from TRAIL-induced apoptosis. These results suggested that a combination of Z-LEHD-FMK and TRAIL selectively killed cancer cells while protecting normal liver cells [1].

In rats with focal ischemia/reperfusion, Z-LEHD-FMK improved neurological outcome by 63% and reduced infarction volume by 49% [2]. In spinal cord trauma rat model, Z-LEHD-FMK reduced apoptotic cell count and protected neurons, myelin, axons, glia and intracellular organelles in the spinal cord [3].

References:
[1].  Ozoren N, Kim K, Burns TF, et al. The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res, 2000, 60(22): 6259-6265.
[2].  Mouw G, Zechel JL, Zhou Y, et al. Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia. Metab Brain Dis, 2002, 17(3): 143-151.
[3].  Colak A, Karaoğlan A, Barut S, et al. Neuroprotection and functional recovery after application of the caspase-9 inhibitor z-LEHD-fmk in a rat model of traumatic spinal cord injury. J Neurosurg Spine, 2005, 2(3): 327-334.

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References on Z-LEHD-FMK

Caspase-9 inhibitor Z-LEHD-FMK enhances the yield of in vitro produced buffalo (Bubalus bubalis) pre-implantation embryos and alters cellular stress response.[Pubmed:26850530]

Res Vet Sci. 2016 Feb;104:4-9.

The present investigation was done to study the effect of caspase-9 inhibitor Z-LEHD-FMK, on in vitro produced buffalo embryos. Z-LEHD-FMK is a cell-permeable, competitive and irreversible inhibitor of enzyme caspase-9, which helps in cell survival. Buffalo ovaries were collected from slaughterhouse and the oocytes were subjected to in vitro maturation (IVM), in vitro fertilization (IVF) and in vitro culture (IVC). The culture medium was supplemented with Z-LEHD-FMK at different concentrations i.e. 0 muM (control), 10 muM, 20 muM, 30 muM and 50 muM during IVM and IVC respectively. After day-2 post-insemination, the cleavage rate was significantly higher (74.20 +/- 5.87% at P<0.05) in the group treated with 20 muM of Z-LEHD-FMK than at any other concentration. Same trend was observed in the blastocyst production rate which was higher at 20 muM (27.42 +/- 2.94% at P<0.05). The blastocysts obtained at day-8 of the culture at different concentrations were subjected to TUNEL assay, to determine the level of apoptosis during the culture medium supplied with 20 muM Z-LEHD-FMK which showed apoptotic index significantly lower (1.88 +/- 0.87 at P<0.05). There was a non-significant increase in total cell number in all Z-LEHD-FMK treated blastocysts. The quantitative gene expression of CHOP and HSP10 genes showed significant increase (P<0.05) in the group treated with 50 muM Z-LEHD-FMK, while, HSP40 showed significant increase (P<0.05) at 30 muM and 50 muM Z-LEHD-FMK concentrations. From the afore mentioned results we conclude that, Z-LEHD-FMK at 20 muM increased the cleavage and blastocyst rate of buffalo pre-implantation embryos also affecting the rate of apoptosis and cellular stress at various concentrations.

The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand.[Pubmed:11103780]

Cancer Res. 2000 Nov 15;60(22):6259-65.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis of transformed and cancer cells but not of most normal cells. Recent studies have revealed an unforeseen toxicity of TRAIL toward normal human hepatocytes, thereby bringing into question the safety of systemic administration of TRAIL in humans with cancer. We found that SW480 colon adenocarcinoma, or H460 non-small cell lung cancer cell lines, which are sensitive to TRAIL, were not protected by the caspase 9 inhibitor Z-LEHD-FMK from TRAIL-induced apoptosis. However, a human colon cancer cell line HCT116 and a human embryonic kidney cell line 293, which are sensitive to TRAIL, were protected by Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 and SW480 cells were protected from TRAIL by the caspase 8 inhibitor Z-IETD-FMK, dominant-negative FADD and cellular FLIP-s and interestingly both cell lines displayed caspase 9 cleavage to a similar extent after TRAIL exposure. We confirmed that normal human liver cells are sensitive to TRAIL. Moreover, we found that normal human liver cells could be protected from TRAIL-induced apoptosis by simultaneous exposure to Z-LEHD-FMK. A similar brief exposure to TRAIL plus Z-LEHD-FMK inhibited colony growth of SW480 but not HCT116 cells. Because some cancer cell lines are not protected from TRAIL-mediated killing by Z-LEHD-FMK, we believe that a brief period of caspase 9 inhibition during TRAIL administration may widen the therapeutic window and allow cancer cell killing while protecting normal liver cells. This strategy could be further developed in the effort to advance TRAIL into clinical trials.

Neuroprotection and functional recovery after application of the caspase-9 inhibitor z-LEHD-fmk in a rat model of traumatic spinal cord injury.[Pubmed:15796358]

J Neurosurg Spine. 2005 Mar;2(3):327-34.

OBJECT: Apoptosis is considered one of the most significant mechanisms in the pathogenesis of neuronal damage after spinal cord injury (SCI). This form of cell death occurs via mediators known as caspases. The aim of this study was to evaluate the neuroprotective effect of the caspase-9 inhibitor, Z-LEHD-FMK, in a rat model of spinal cord trauma. METHODS: Fifty-four Wistar albino rats were studied in the following three groups of 18 animals each: sham-operated controls (Group 1); trauma-only controls (Group 2); and trauma combined with Z-LEHD-FMK-treated animals (0.8 microM/kg; Group 3). Spinal cord injury was produced at the thoracic level by using the weight-drop technique. Responses to SCI and the efficacy of Z-LEHD-FMK treatment were determined on the basis of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining and light and electron microscopy findings in cord tissue at 24 hours and 7 days posttrauma. Six rats from each group were also assessed for functional recovery at 3 and 7 days after SCI. This was conducted using the inclined-plane technique and a modified version of the Tarlov motor grading scale. At 24 hours postinjury, light microscopic examination of Group 2 tissue samples showed hemorrhage, edema, necrosis, polymorphonuclear leukocyte infiltration, and vascular thrombi. Those obtained in Group 3 rats at this stage showed similar features. At 24 hours postinjury, the mean apoptotic cell count in Group 2 was significantly higher than that in Group 3 (90.25 +/- 2.6 and 50.5 +/- 1.9, respectively; p < 0.05). At 7 days postinjury, the corresponding mean apoptotic cell counts were 49 +/- 2.1 and 17.7 +/- 2.6, also a significant difference (p < 0.05). Electron microscopy findings confirmed the occurrence of programmed cell death in different cell types in the spinal cord and showed that Z-LEHD-FMK treatment protected neurons, glia, myelin, axons, and intracellular organelles. CONCLUSIONS: Examination of the findings in this rat model of SCI revealed that apoptosis occurs not only in neurons and astrocytes but also in oligodendrocytes and microglia. Furthermore, immediate treatment with the caspase-9 inhibitor Z-LEHD-FMK blocked apoptosis effectively and was associated with better functional outcome. More in-depth research of the role of programmed cell death in spinal cord trauma and further study of the ways in which caspases are involved in this process may lead to new strategies for treating SCI.

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