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| 5mg | |||
| Other Sizes |
| Targets |
GNA002 targets EZH2 (Enhancer of zeste homolog 2), the catalytic subunit of the Polycomb repressive complex 2 (PRC2). EZH2 is a histone methyltransferase that catalyzes the methylation of histone H3 at lysine 27 (H3K27), a histone mark associated with transcriptional repression. EZH2 is frequently overexpressed or mutated in various cancers and is associated with poor prognosis. By covalently binding to Cys668 in the EZH2-SET domain with an IC50 of 1.1 microM, GNA002 inhibits EZH2 enzymatic activity and triggers EZH2 degradation through CHIP-mediated ubiquitination. GNA002 is a potent, selective, covalent EZH2 inhibitor used in epigenetic research.
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| ln Vitro |
The proliferation of multiple nail lines is significantly inhibited by GNA002 (10 μM; 72 hours); the IC50s for MV4-11 and RS4-11, respectively, are 0.070 μM and 0.103 μM. In the case of human cancer, GNA002 (2 μM; 24 hours) and GNA002 (0.1-4 μM; 48 hours) both efficiently inhibit the H3K27 trimethylation of Cal-27 in the head and neck bones caused by EZH2 [1]. The capacity of cells to cause cell death is greater [1]. Examine[1]
GNA002 demonstrates potent in vitro activity as an EZH2 inhibitor. The compound has an IC50 of 1.1 microM against EZH2. GNA002 can specifically and covalently bind to Cys668 in the EZH2-SET domain to induce EZH2 degradation through CHIP-mediated ubiquitination. Its activity is concentration-dependent, with potent inhibition observed at micromolar concentrations. GNA002 is a potent, selective, covalent inhibitor of EZH2 used in biochemical and cellular research to probe histone methyltransferase function and epigenetic regulation. Its covalent binding mechanism provides sustained inhibition of EZH2 activity. |
| ln Vivo |
Both the H3K27Me3 in tumor tissue and the Cal-27-derived tumor volume were markedly decreased by GNA002 (Manhattan; 100 mg/kg; daily). Additionally, GNA002 levels were markedly suppressed in the periphery of Daudi and Pfeiffer cells, which are xenografted A549 lung cancer cells. At least in xenograft experimental models, GNA002 reduces the aberrant core function of EZH2, which in turn inhibits tumor growth in vivo [1].
In vivo, GNA002 has been studied for its potential to inhibit EZH2 and modulate epigenetic regulation. As a covalent EZH2 inhibitor that induces EZH2 degradation, the compound would be expected to reduce H3K27 methylation and alter gene expression programs. EZH2 inhibitors have been studied in various animal models of cancer, where they have demonstrated efficacy in reducing tumor growth and metastasis. GNA002's in vivo activity has been described in research publications. The compound's ability to covalently bind and degrade EZH2 makes it a valuable tool for epigenetic research. |
| Enzyme Assay |
In vitro enzyme assays for GNA002 involve measuring the inhibition of EZH2 methyltransferase activity. Recombinant EZH2 complex (PRC2) is incubated with varying concentrations of the test compound, S-adenosylmethionine (SAM), and a histone H3 peptide substrate or nucleosomes. The transfer of methyl groups to H3K27 is quantified using radiometric detection with [3H]-SAM, or by using a luminescent method such as the AlphaScreen or TR-FRET assay that detects methylated H3K27. IC50 values are calculated by plotting percent inhibition against compound concentration using non-linear regression analysis. The compound has an IC50 of 1.1 microM. Covalent binding to Cys668 can be assessed by mass spectrometry or by using mutant EZH2 proteins. Each concentration is typically tested in duplicate or triplicate.
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| Cell Assay |
Test[1]
Cell Types: Various cancer cell lines Tested Concentrations: 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Inhibits the proliferation of various cancer cell lines, the IC50 of MV4-11 and RS4-11 are 0.070 μM and 0.103 μM respectively. Apoptosis analysis [1] Cell Types: HN-4 and Cal-27 head and neck cancer cells Tested Concentrations: 2 μM Incubation Duration: 24 hrs (hours) Experimental Results: Induction of apoptosis in human cancer cells. Western Blot Analysis[1] Cell Types: Cal-27 Head and Neck Cancer Cells Tested Concentrations: 0.1, 0.2, 0.5, 1, 2, 4 μM Incubation Duration: 48 hrs (hours) Experimental Results: diminished H3K27Me3 levels. In vitro cellular assays for GNA002 are performed using cancer cell lines. Cells are treated with varying concentrations of the compound for defined time periods. EZH2 protein levels are assessed by Western blot using EZH2-specific antibodies. H3K27me3 levels are assessed by Western blot using methylation-specific antibodies. EZH2 target gene expression is measured by qRT-PCR. Cell proliferation and viability are measured using MTT or CellTiter-Glo assays. Apoptosis is measured using annexin V/propidium iodide staining or caspase activity assays. Cell cycle analysis is performed by flow cytometry following propidium iodide staining. Cytotoxicity is assessed in parallel to ensure that observed effects are not due to cell death. IC50 values for inhibition of cell proliferation are calculated from dose-response curves. |
| Animal Protocol |
Animal/Disease Models: Male BALB/C nude mice, 30-35 days old, weighing 18-22 g, carrying Cal-27 xenograft tumors [1]
Doses: 100 mg/kg Doses: oral; daily Experimental Results: Cal-27 The size and weight of tumors formed by cells are diminished. In vivo animal studies for GNA002 are conducted using mouse xenograft models of cancer. Immunodeficient mice are implanted subcutaneously with cancer cells. Once tumors reach a predetermined size, animals are randomized into treatment groups and administered GNA002 via oral gavage or intraperitoneal injection at various doses and schedules. Tumor growth is measured using calipers. EZH2 protein levels and H3K27me3 levels are assessed in tumor tissues by immunohistochemistry or Western blot. Pharmacokinetic studies assess drug concentrations in plasma and tumor tissues. Animals are monitored for clinical signs and body weight. Efficacy is expressed as tumor growth inhibition compared to vehicle-treated controls. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of GNA002 have been characterized in preclinical studies. The compound has a molecular formula of C42H55NO8 and a molecular weight of 701.89 g/mol. Its chemical name is (2Z)-4-[(1S,2S,13S,15R)-7-[(
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| References |
| Molecular Formula |
C42H55NO8
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| Molecular Weight |
701.888013124466
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| Exact Mass |
701.392
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| CAS # |
1385035-79-9
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| PubChem CID |
162642890
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| Appearance |
Light yellow to yellow ointment
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| LogP |
7.9
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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 |
14
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| Heavy Atom Count |
51
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| Complexity |
1530
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CCOCCNC(=O)/C(=C/CC12C(=O)C3CC(C14C(=C3)C(=O)C5=C(C(=C(C(=C5O4)CC=C(C)C)O)C/C=C(\C)/CCC=C(C)C)O)C(O2)(C)C)/C
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| InChi Key |
HJJVIXXMFVHPER-PIZOZCJOSA-N
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| InChi Code |
InChI=1S/C42H55NO8/c1-10-49-21-20-43-39(48)27(7)18-19-41-38(47)28-22-31-36(46)33-35(45)29(17-15-26(6)13-11-12-24(2)3)34(44)30(16-14-25(4)5)37(33)50-42(31,41)32(23-28)40(8,9)51-41/h12,14-15,18,22,28,32,44-45H,10-11,13,16-17,19-21,23H2,1-9H3,(H,43,48)/b26-15+,27-18+
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| Chemical Name |
(E)-4-[7-[(2E)-3,7-dimethylocta-2,6-dienyl]-6,8-dihydroxy-17,17-dimethyl-5-(3-methylbut-2-enyl)-10,14-dioxo-3,16-dioxapentacyclo[11.4.1.02,11.02,15.04,9]octadeca-4,6,8,11-tetraen-15-yl]-N-(2-ethoxyethyl)-2-methylbut-2-enamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~25 mg/mL (~35.62 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (1.78 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 12.5 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: 1.25 mg/mL (1.78 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 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.4247 mL | 7.1236 mL | 14.2472 mL | |
| 5 mM | 0.2849 mL | 1.4247 mL | 2.8494 mL | |
| 10 mM | 0.1425 mL | 0.7124 mL | 1.4247 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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