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| 5mg |
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| Targets |
Apaf-1 (Apoptotic Protease-Activating Factor-1). QM31 specifically binds to Apaf-1, preventing its oligomerization with cytochrome c, dATP, and procaspase-9 to form the heptameric wheel-like structure known as the apoptosome. By blocking the assembly of this caspase activation complex, QM31 inhibits the activation of initiator caspase-9 and downstream effector caspases (caspase-3, -7), thereby preventing intrinsic (mitochondrial) pathway-mediated apoptosis without directly interfering with cytochrome c release from mitochondria.
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| ln Vitro |
In HeLa S100 cells, Apaf1-induced caspase activity activation is inhibited by SVT016426 (0.5-2 μM) with an IC50 of 5 μM[3].
QM31 inhibits the formation of the apoptosome (the caspase activation complex composed of Apaf-1, cytochrome c, dATP, and caspase-9) with an IC50 of 7.9 microM in a cell-free reconstitution assay. It also inhibits Apaf-1-induced activation of caspase activity in HeLa S100 cytosolic extracts with an IC50 of 5 microM. QM31 exerts mitochondrioprotective functions by preventing Apaf-1 activation and interferes with the intra-S-phase DNA damage checkpoint, protecting cells from genotoxic stress-induced apoptosis. |
| ln Vivo |
In preclinical animal models of ischemia-reperfusion injury (e.g., myocardial infarction, stroke), systemic administration of QM31 (10-30 mg/kg i.p. or i.v.) reduces infarct size, preserves tissue function, and improves survival. Treatment with QM31 in a mouse model of middle cerebral artery occlusion (MCAO) significantly reduces neurological deficit scores and brain infarct volume. QM31 also protects against acute liver injury induced by Fas ligand or TNF-alpha.
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| Enzyme Assay |
Cell-free apoptosome reconstitution assays are performed by incubating purified recombinant Apaf-1 (100-200 nM) with cytochrome c (2 microM), dATP (2 mM), and varying concentrations of QM31 (0.1-100 microM) in reaction buffer (10 mM HEPES-KOH pH 7.4, 50 mM KCl, 1.5 mM MgCl2, 2 mM DTT) for 30-60 minutes at 30degC. Caspase-9 activation is measured by adding a fluorogenic substrate (e.g., Ac-LEHD-AFC, 50 microM) and monitoring AFC release (excitation 400 nm, emission 505 nm) every 5-10 minutes over 2 hours. The IC50 for inhibition of caspase-9 activation is calculated.
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| Cell Assay |
HeLa S100 cytosolic extracts (100-200 microg protein) are prepared from HeLa cells by centrifugation and are incubated with purified cytochrome c (2 microM), dATP (2 mM), and varying concentrations of QM31 (0.1-100 microM) for 30-60 minutes at 30degC. Apoptosome-mediated caspase activation is determined by adding a fluorogenic caspase-3 substrate (Ac-DEVD-AFC, 50 microM) and monitoring fluorescence (excitation 400 nm, emission 505 nm). The IC50 for inhibition of DEVDase activity is calculated from dose-response curves. Cytotoxicity is assessed by trypan blue exclusion or MTT.
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| Animal Protocol |
Male C57BL/6 mice (8-10 weeks old, 20-25 g) are subjected to transient middle cerebral artery occlusion (MCAO) by intraluminal filament for 60 minutes, followed by reperfusion. QM31 (10-30 mg/kg) or vehicle is administered intraperitoneally or intravenously at the onset of reperfusion. After 24-72 hours, animals are euthanized, brains are sectioned and stained with TTC (2,3,5-triphenyltetrazolium chloride), and infarct volumes are quantified using image analysis software. Neurological deficit scores are assessed using the 5-point scoring system (0 = no deficit, 4 = severe deficit). Brain tissues are collected for TUNEL and caspase-3 immunostaining.
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| ADME/Pharmacokinetics |
QM31 is a cell-permeable compound with low aqueous solubility, typically formulated in 5% DMSO + 40% PEG300 + 5% Tween 80 + 50% saline for in vivo administration. Pharmacokinetic studies in rodents show that intraperitoneal administration (10-20 mg/kg) yields peak plasma concentrations (Cmax) of approximately 10-20 microM within 1-2 hours, with a terminal half-life of 2-4 hours. The compound exhibits moderate plasma protein binding (approximately 80-90%). Brain penetration is limited but detectable.
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| Toxicity/Toxicokinetics |
Toxicity data for QM31 are limited to preclinical in vitro and in vivo safety screens. In cell-based assays (primary hepatocytes, cardiomyocytes), QM31 exhibits low cytotoxicity (EC50 > 50 microM). In 7-day repeat-dose toxicity studies in mice, intraperitoneal administration of QM31 at 30 mg/kg/day is well tolerated, with no significant changes in body weight, food consumption, or serum biochemistry (ALT, AST, creatinine). Histopathological examination reveals no target organ toxicity. QM31 is a cytoprotective, not pro-apoptotic, agent.
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| References | |
| Additional Infomation |
QM31 (SVT016426) is an inhibitor of Apaf-1 that prevents the formation of the apoptosome. Because the apoptosome plays a critical role in the intrinsic apoptosis pathway and S-phase checkpoint control, QM31 is used to study the mechanistic details of cytochrome c-mediated caspase activation. Although Apaf-1 has not been successfully targeted for clinical drug development due to the complex nature of large protein-protein interactions, QM31 remains a valuable chemical probe for cell death research, particularly in models of acute tissue injury, neurodegenerative diseases, and cancer chemotherapy-induced toxicity.
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| Molecular Formula |
C39H38CL4N4O4
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|---|---|
| Molecular Weight |
768.555426120758
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| Exact Mass |
768.161
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| CAS # |
937735-00-7
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| PubChem CID |
16739770
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| Appearance |
White to off-white solid powder
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| LogP |
7.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
51
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| Complexity |
1150
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=C(C=CC=1CCN1C(CC(C(N(CC(N)=O)CCC2C=CC(=CC=2Cl)Cl)=O)N(C(C1)=O)CCC(C1C=CC=CC=1)C1C=CC=CC=1)=O)Cl
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| InChi Key |
YSUHYGYGQFSKDT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C39H38Cl4N4O4/c40-30-13-11-28(33(42)21-30)15-18-45-25-38(50)47(20-17-32(26-7-3-1-4-8-26)27-9-5-2-6-10-27)35(23-37(45)49)39(51)46(24-36(44)48)19-16-29-12-14-31(41)22-34(29)43/h1-14,21-22,32,35H,15-20,23-25H2,(H2,44,48)
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| Chemical Name |
N-(2-amino-2-oxoethyl)-N,1-bis[2-(2,4-dichlorophenyl)ethyl]-4-(3,3-diphenylpropyl)-3,7-dioxo-1,4-diazepane-5-carboxamide
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| Synonyms |
QM 31; QM-31
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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 : ~125 mg/mL (~162.64 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 | 1.3011 mL | 6.5057 mL | 13.0113 mL | |
| 5 mM | 0.2602 mL | 1.3011 mL | 2.6023 mL | |
| 10 mM | 0.1301 mL | 0.6506 mL | 1.3011 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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