GSK503EZH2 inhibitor CAS# 1346572-63-1 |
Quality Control & MSDS
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| Cas No. | 1346572-63-1 | SDF | Download SDF |
| PubChem ID | 67469117 | Appearance | Powder |
| Formula | C31H38N6O2 | M.Wt | 526.67 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 44 mg/mL (83.54 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-3-methyl-6-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1-propan-2-ylindole-4-carboxamide | ||
| SMILES | CC1=CC(=C(C(=O)N1)CNC(=O)C2=C3C(=CN(C3=CC(=C2)C4=CN=C(C=C4)N5CCN(CC5)C)C(C)C)C)C | ||
| Standard InChIKey | HRDQQHUKUIKFHT-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C31H38N6O2/c1-19(2)37-18-21(4)29-25(30(38)33-17-26-20(3)13-22(5)34-31(26)39)14-24(15-27(29)37)23-7-8-28(32-16-23)36-11-9-35(6)10-12-36/h7-8,13-16,18-19H,9-12,17H2,1-6H3,(H,33,38)(H,34,39) | ||
| 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. |
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| 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. |
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| 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. | ||
| Description | GSK503 is a potent and specific inhibitor of EZH2 methyltransferase with Kiapp values of 3 to 27 nM.In Vitro:GSK503 inhibits the methyltransferase activity of wild type and mutant EZH2 with similar potency (Kiapp=3-27 nM) and is structurally related to GSK126 and GSK343. GSK503 is >200 fold selective over EZH1 (Kiapp=636 nM) and >4000 fold selective over other histone methyltransferases[1].In Vivo:In a melanoma mouse model, conditional EZH2 ablation as much as treatment with the GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology[2]. GSK503 displays favorable pharmacokinetics in mice. GSK503, but not vehicle, prevents the formation of germinal center after SRBC or NP-KLH immunization, phenocopying the Ezh2 null phenotype. GSK503 treatment leads to reduced numbers of GC B-cells by flow cytometry, reduces number and volume of GCs by immunohistochemistry, and impairs formation high affinity antibodies[1]. References: | |||||
GSK503 Dilution Calculator
GSK503 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.8987 mL | 9.4936 mL | 18.9872 mL | 37.9744 mL | 47.4681 mL |
| 5 mM | 0.3797 mL | 1.8987 mL | 3.7974 mL | 7.5949 mL | 9.4936 mL |
| 10 mM | 0.1899 mL | 0.9494 mL | 1.8987 mL | 3.7974 mL | 4.7468 mL |
| 50 mM | 0.038 mL | 0.1899 mL | 0.3797 mL | 0.7595 mL | 0.9494 mL |
| 100 mM | 0.019 mL | 0.0949 mL | 0.1899 mL | 0.3797 mL | 0.4747 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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GSK503 is a potent inhibitor of EZH2.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme that catalyses trimethylation of lysine 27 in histone 3 (H3K27me3), and then induces chromatin compaction and consequently inhibits target genes transcription.
GSK503 is a potent EZH2 inhibitor with anticancer activity. In human melanoma cells, GSK503 significantly reduced H3K27me3 levels, induced G1 cell cycle arrest and slowed down cell growth [1].
In mice, GSK503 induced reversible weight loss by ~10%. In mice with skin melanomas, GSK503 reduced H3K27me3 levels in tumour and stromal cells, and significantly reduced the emergence of new skin melanomas. Also, GSK503 significantly inhibited the proliferation of tumour cells. In C57Bl/6 mice xenografted murine B16-F10 melanoma cells, GSK503 significantly reduced H3K27me3 levels and inhibited tumor growth. Also, GSK503 inhibited lymph node and lung metastases of melanoma and reduced lung nodule counts. GSK503 increased the expression of deoxycytidine kinase (DCK), adenosylmethionine decarboxylase 1 (AMD1) and WD repeat domain 19 (WDR19), which were EZH2 target genes [1].
Reference:
[1]. Zingg D, Debbache J, Schaefer SM, et al. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat Commun, 2015, 6: 6051.
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Overexpression of EZH2 in conjunctival melanoma offers a new therapeutic target.[Pubmed:29732557]
J Pathol. 2018 Aug;245(4):433-444.
Malignant melanoma of the conjunctiva (CM) is an uncommon but potentially deadly disorder. Many malignancies show an increased activity of the epigenetic modifier enhancer of zeste homolog 2 (EZH2). We studied whether EZH2 is expressed in CM, and whether it may be a target for therapy in this malignancy. Immunohistochemical analysis showed that EZH2 protein expression was absent in normal conjunctival melanocytes and primary acquired melanosis, while EZH2 was highly expressed in 13 (50%) of 26 primary CM and seven (88%) of eight lymph node metastases. Increased expression was positively associated with tumour thickness (p =0.03). Next, we targeted EZH2 with specific inhibitors (GSK503 and UNC1999) or depleted EZH2 by stable shRNA knockdown in three primary CM cell lines. Both pharmacological and genetic inactivation of EZH2 inhibited cell growth and colony formation and influenced EZH2-mediated gene transcription and cell cycle profile in vitro. The tumour suppressor gene p21/CDKN1A was especially upregulated in CM cells after EZH2 knockdown in CM cells. Additionally, the potency of GSK503 against CM cells was monitored in zebrafish xenografts. GSK503 profoundly attenuated tumour growth in CM xenografts at a well-tolerated concentration. Our results indicate that elevated levels of EZH2 are relevant to CM tumourigenesis and progression, and that EZH2 may become a potential therapeutic target for patients with CM. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors.[Pubmed:25609585]
Nat Commun. 2015 Jan 22;6:6051.
Increased activity of the epigenetic modifier EZH2 has been associated with different cancers. However, evidence for a functional role of EZH2 in tumorigenesis in vivo remains poor, in particular in metastasizing solid cancers. Here we reveal central roles of EZH2 in promoting growth and metastasis of cutaneous melanoma. In a melanoma mouse model, conditional Ezh2 ablation as much as treatment with the preclinical EZH2 inhibitor GSK503 stabilizes the disease through inhibition of growth and virtually abolishes metastases formation without affecting normal melanocyte biology. Comparably, in human melanoma cells, EZH2 inactivation impairs proliferation and invasiveness, accompanied by re-expression of tumour suppressors connected to increased patient survival. These EZH2 target genes suppress either melanoma growth or metastasis in vivo, revealing the dual function of EZH2 in promoting tumour progression. Thus, EZH2-mediated epigenetic repression is highly relevant especially during advanced melanoma progression, which makes EZH2 a promising target for novel melanoma therapies.
