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QNZ (EVP4593; CAY10470)

Alias: CAY10470; CAY 10470; CAY-10470; EVP 4593; 545380-34-5; 6-Amino-4-(4-phenoxyphenylethylamino)quinazoline; QNZ; EVP4593; QNZ (EVP4593); N4-(4-phenoxyphenethyl)quinazoline-4,6-diamine; 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine; NF-kB activation inhibitor; EVP-4593; EVP4593; QNZ
Cat No.:V0038 Purity: ≥98%
QNZ (also known as EVP-4593 or CAY-10470),a quinazoline derivative, is a novel and potentNF-κB inhibitor, which shows potent inhibitory activity toward both NF-κB activation and TNF-α production with IC50 of 11 nM and 7 nM in human Jurkat T cells, respectively.
QNZ (EVP4593; CAY10470)
QNZ (EVP4593; CAY10470) Chemical Structure CAS No.: 545380-34-5
Product category: TNFa
This product is for research use only, not for human use. We do not sell to patients.
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InvivoChem's QNZ (EVP4593; CAY10470) has been cited by 1 publication
Purity & Quality Control Documentation

Purity: ≥98%

Product Description

QNZ (also known as EVP-4593 or CAY-10470), a quinazoline derivative, is a novel and potent NF-κB inhibitor, which shows potent inhibitory activity toward both NF-κB activation and TNF-α production with IC50 of 11 nM and 7 nM in human Jurkat T cells, respectively. It was eliminated using human Jurkat T cells in a luciferase reporter gene-based assay. EVP4593 had neuroprotective effects on GMSLNs in HD and decreased the number of lysosomes/autophagosomes and SOC currents. EVP4593 might be an effective HD medication.

Biological Activity I Assay Protocols (From Reference)
Targets
TNF-α (IC50 = 7 nM); NF-κB (IC50 = 11 nM)
ln Vitro
QNZ (Compound 11q) has an anti-inflammatory effect that inhibits the NF-B mediated response. Edema formation is dose-dependently inhibited by QNZ[1]. In Huntington's disease (HD), QNZ (EVP4509) lowers the quantity of lysosomes/autophagosomes and store-operated channel (SOC) currents. It is anticipated that normalizing calcium transport within neurons in response to QNZ will lessen pathology manifestation. Using transmission electron microscopy (TEM), several lysosomes/autophagosomes are examined in HD and WT neurons treated with QNZ. While WT neurons are unaffected, incubation with QNZ almost doubles the amount of lysosomes/autophagosomes in HD GABAergic Medium Spiny (GABA MS)-like Neurons (GMSLNs) (from 0.41±0.04 to 0.23±0.04; p<0.05). By using flow cytometry (FC) analysis to look at lysosome content, this observation is confirmed. In HD GMSLNs, the median fluorescence intensity decreases by 34±6 percent after QNZ treatment (p<0.05)[2].
ln Vivo
In Huntington's disease (HD), mutant Huntingtin (mHtt) protein causes striatal neuron dysfunction, synaptic loss, and eventual neurodegeneration. To understand the mechanisms responsible for synaptic loss in HD, we developed a corticostriatal coculture model that features age-dependent dendritic spine loss in striatal medium spiny neurons (MSNs) from YAC128 transgenic HD mice. Age-dependent spine loss was also observed in vivo in YAC128 MSNs. To understand the causes of spine loss in YAC128 MSNs, we performed a series of mechanistic studies. We previously discovered that mHtt protein binds to type 1 inositol (1,4,5)-trisphosphate receptor (InsP3R1) and increases its sensitivity to activation by InsP3. We now report that the resulting increase in steady-state InsP3R1 activity reduces endoplasmic reticulum (ER) Ca(2+) levels. Depletion of ER Ca(2+) leads to overactivation of the neuronal store-operated Ca(2+) entry (nSOC) pathway in YAC128 MSN spines. The synaptic nSOC pathway is controlled by the ER resident protein STIM2. We discovered that STIM2 expression is elevated in aged YAC128 striatal cultures and in YAC128 mouse striatum. Knock-down of InsP3R1 expression by antisense oligonucleotides or knock-down or knock-out of STIM2 resulted in normalization of nSOC and rescue of spine loss in YAC128 MSNs. The selective nSOC inhibitor EVP4593 was identified in our previous studies. We now demonstrate that EVP4593 reduces synaptic nSOC and rescues spine loss in YAC128 MSNs. Intraventricular delivery of EVP4593 in YAC128 mice rescued age-dependent striatal spine loss in vivo. Our results suggest EVP4593 and other inhibitors of the STIM2-dependent nSOC pathway as promising leads for HD therapeutic development.[3]
EVP4593 (1 mg/kg, i.p.) dose-dependently inhibits carrageenin-induced paw edema in rats.
Enzyme Assay
In RPMI1640 with 10% FCS, human Jurkat T cells are cultured at 37 °C in a 5% CO2 environment. The cells are transiently transfected with 1 μg of pNFκB-Luc using the SuperFect Transfection Reagent after being plated in 6-well plates (2×106/well). The cells undergo overnight culture at 37°C following transfection. Then, they are collected, resuspended in new medium, and plated in 96-well plates (2×105/well). The cells are placed in 96-well plates, and EVP4593 is dissolved in DMSO and added at the proper concentrations. The plates are then incubated at 37°C for an hour. For the purpose of triggering transcription, 10 ng/mL of PMA and 100 μg/mL of PHA are added to each well, and the cells are then incubated for an additional 6 hours at 37°C. Cell lysis buffer containing luciferase substrate is added to each well after the culture media have been removed. The luminescence is then immediately measured with a Packard Topcount after each portion has been transferred to a black 96-well plate. A nonlinear regression technique is used to determine the 50% inhibitory concentration (IC50) values.
Cell Assay
iPSHD22 cells are cultured in K-4 medium in a 96-well black plates with clear flat bottom. Before being analyzed, cells are then exposed to chemicals for 24 hours (for example, QNZ 100 nM). Luminescent assay To simultaneously count the proportion of alive (viability) and dead (cytotoxicity) cells in each well, the MultiTox-Fluor Multiplex Cytotoxicity Assay is used. DTX 880 Multimode Microplate Reader is used to find fluorescence. Using the equation ([cytotoxicity in a well with cells]-([cytotoxicity in a well without cells])/([viability in a well with cells]-([viability in a well without cells])[2], the level of cell death (LoCD) is assessed.
Animal Protocol
0.5% hydroxypropyl cellulose; 1 mg/kg; i.p injection
male SD rats with carrageenin induced paw edema
References

[1]. Discovery of quinazolines as a novel structural class of potent inhibitors of NF-kappa B activation.

[2]. Manifestation of Huntington's disease pathology in human induced pluripotent stem cell-derived neurons. Mol Neurodegener. 2016 Apr 14;11:27.

[3]. Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model. J Neurosci. 2016 Jan 6;36(1):125-41.

Additional Infomation
We disclose here a new structural class of low-molecular-weight inhibitors of NF-kappa B activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-kappa B transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-kappa B transcriptional activation and TNF-alpha production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.[1]
Background: Huntington's disease (HD) is an incurable hereditary neurodegenerative disorder, which manifests itself as a loss of GABAergic medium spiny (GABA MS) neurons in the striatum and caused by an expansion of the CAG repeat in exon 1 of the huntingtin gene. There is no cure for HD, existing pharmaceutical can only relieve its symptoms. Results: Here, induced pluripotent stem cells were established from patients with low CAG repeat expansion in the huntingtin gene, and were then efficiently differentiated into GABA MS-like neurons (GMSLNs) under defined culture conditions. The generated HD GMSLNs recapitulated disease pathology in vitro, as evidenced by mutant huntingtin protein aggregation, increased number of lysosomes/autophagosomes, nuclear indentations, and enhanced neuronal death during cell aging. Moreover, store-operated channel (SOC) currents were detected in the differentiated neurons, and enhanced calcium entry was reproducibly demonstrated in all HD GMSLNs genotypes. Additionally, the quinazoline derivative, EVP4593, reduced the number of lysosomes/autophagosomes and SOC currents in HD GMSLNs and exerted neuroprotective effects during cell aging. Conclusions: Our data is the first to demonstrate the direct link of nuclear morphology and SOC calcium deregulation to mutant huntingtin protein expression in iPSCs-derived neurons with disease-mimetic hallmarks, providing a valuable tool for identification of candidate anti-HD drugs. Our experiments demonstrated that EVP4593 may be a promising anti-HD drug. Keywords: Aging; Differentiation; GABAergic medium spiny neurons; Human induced pluripotent stem cells; Huntington’s disease; Neurodegeneration; Neuroprotection; Nuclear indentations; Store-operated calcium entry.[2]
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C22H20N4O
Molecular Weight
356.42
Exact Mass
356.163
Elemental Analysis
C, 74.14; H, 5.66; N, 15.72; O, 4.49
CAS #
545380-34-5
Related CAS #
545380-34-5
PubChem CID
509554
Appearance
Light green to green solid powder
Density
1.3±0.1 g/cm3
Boiling Point
602.0±55.0 °C at 760 mmHg
Melting Point
169-175ºC
Flash Point
317.9±31.5 °C
Vapour Pressure
0.0±1.7 mmHg at 25°C
Index of Refraction
1.714
LogP
4.57
Hydrogen Bond Donor Count
2
Hydrogen Bond Acceptor Count
5
Rotatable Bond Count
6
Heavy Atom Count
27
Complexity
434
Defined Atom Stereocenter Count
0
SMILES
O(C1C([H])=C([H])C([H])=C([H])C=1[H])C1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C([H])([H])N([H])C1C2C([H])=C(C([H])=C([H])C=2N=C([H])N=1)N([H])[H]
InChi Key
IBAKVEUZKHOWNG-UHFFFAOYSA-N
InChi Code
InChI=1S/C22H20N4O/c23-17-8-11-21-20(14-17)22(26-15-25-21)24-13-12-16-6-9-19(10-7-16)27-18-4-2-1-3-5-18/h1-11,14-15H,12-13,23H2,(H,24,25,26)
Chemical Name
4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine
Synonyms
CAY10470; CAY 10470; CAY-10470; EVP 4593; 545380-34-5; 6-Amino-4-(4-phenoxyphenylethylamino)quinazoline; QNZ; EVP4593; QNZ (EVP4593); N4-(4-phenoxyphenethyl)quinazoline-4,6-diamine; 4-N-[2-(4-phenoxyphenyl)ethyl]quinazoline-4,6-diamine; NF-kB activation inhibitor; EVP-4593; EVP4593; QNZ
HS Tariff Code
2934.99.9001
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)
Solubility Data
Solubility (In Vitro)
DMSO: ~5 mg/mL warming (~14.0 mM)
Water: <1 mg/mL (slightly soluble or insoluble)
Ethanol: <1 mg/mL (slightly soluble or insoluble)
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.01 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 (7.01 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.01 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly.


Solubility in Formulation 4: 0.5% hydroxyethyl cellulose: 30 mg/mL

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.8057 mL 14.0284 mL 28.0568 mL
5 mM 0.5611 mL 2.8057 mL 5.6114 mL
10 mM 0.2806 mL 1.4028 mL 2.8057 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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
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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.

Biological Data
  • Reduction of SOC entry activity in HD GMSLNs by EVP4595. Mol Neurodegener . 2016 Apr 14;11:27.
  • Protection of aging HD GMSNLNs from premature cell death. a The number of autophagosomes/lysosomes per μm2 in WT (hESM01) and HD (iPSHD22) GMSLNs after EVP4593 (1 μM) treatment for 14 h. Mol Neurodegener . 2016 Apr 14;11:27.
  • The nSOC inhibitor EVP4593 normalizes YAC128 MSN spine SOC entry. J Neurosci . 2016 Jan 6;36(1):125-41.
  • The SOC inhibitor EVP4593 rescues YAC128 MSN spines both in vitro and in vivo. J Neurosci . 2016 Jan 6;36(1):125-41.
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