Antibodies
EPZ-6438
- 貨號 Cat. No.
- S7128
- 規格 Size
- 10mgã€50mg
- 品牌 Brand
- Selleckchem
Description
EPZ-6438
Catalog No.S7128
EPZ-6438 is a potent, and selective EZH2 inhibitor with Ki and IC50 of 2.5 nM and 11 nM, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | EPZ-6438 is a potent, and selective EZH2 inhibitor with Ki and IC50 of 2.5 nM and 11 nM, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs. | |||||
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| Targets | EZH2 | EZH2 | ||||
| IC50 | 11 nM | 2.5 nM (Ki) [1] | ||||
| In vitro | EPZ-6438 concentration-dependently reduces global H3K27Me3 levels in wild-type or SMARCB1 mutant cells, and induces strong antiproliferative effects with IC50 ranging from 32 nM to 1000 nM in SMARCB1-deleted MRT cell lines. EPZ-6438 induces gene expression of neuronal differentiation and cell cycle inhibition, while inhibtis expression of Hedgehog pathway genes, MYC and EZH2. [1] The antiproliferative effect of EPZ-6438 is enhanced by either prednisolone or dexamethasone in several EZH2 mutant lymphoma cell lines. [2] | |||||
| In vivo | In SCID mice bearing s.c. G401 xenografts, EPZ-6438 induces tumor stasis during the administration period and produces a significant tumor growth delay with minimal effect on body weight. [1] | |||||
| Features | Orally bioavailable EZH2-selective inhibitor for both wild-type and mutant. Currently being tested in Phase II clinical trials for treatment of Diffuse Large B Cell Lymphoma. | |||||
Protocol(Only for Reference)
Kinase Assay: [1]
| Biochemical Methods | EPZ-6438 is incubated for 30 min with 40 μL per well of 5 nM PRC2 (final assay concentration in 50 μL is 4 nM ) in 1X assay buffer (20 mM Bicine [pH 7.6], 0.002% Tween-20, 0.005% Bovine Skin Gelatin and 0.5 mM DTT). 10 μL per well of substrate mix comprising assay buffer 3 H-SAM, unlabeled SAM, and peptide representing histone H3 residues 21-44 containing C-terminal biotin (appended to a C-terminal amide-capped lysine) are added to initiate the reaction (both substrates are present in the final reaction mixture at their respective Km values, an assay format referred to as balanced conditions. The final concentrations of substrates and methylation state of the substrate peptide are indicated for each enzyme Reactions are incubated for 90 min at room temperature and quenched with 10 μL per well of 600 μM unlabeled SAM, Then transferred to a 384-well flashplate and washed after 30 min. |
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Cell Assay: [1]
| Cell lines | Mutant cell lines (G401, A204, G402, KYM-1), Wild type cell line (RD, 293, SJCRH30) |
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| Concentrations | ~10 μM |
| Incubation Time | 7 days |
| Method | For the adherent cell line proliferation assays, plating densities for each cell line are determined based on growth curves (measured by ATP content) and density over a 7-d time course. On the day before compound treatment, cells are plated in either 96-well plates in triplicate (for the day 0–7 time course) or 6-well plates (for replating on day 7 for the remainder of the time course). On day 0, cells are either untreated, DMSO-treated, or treated with EPZ-6438 starting at 10 µM and decreasing in either threefold or fourfold dilutions. Plates are read on day 0, day 4, and day 7 using Cell Titer Glo, with compound/media being replenished on day 4. On day 7, the six-well plates are trypsinized, centrifuged, and resuspended in fresh media for counting by Vi-Cell. Cells from each treatment are replated at the original density in 96-well plates in triplicate. Cells are allowed to adhere to the plate overnight, and cells are treated as on day 0. On days 7, 11, and 14, plates are read using Cell Titer Glo, with compound/media being replenished on day 11. Averages of triplicates are used to plot proliferation over the time course, and calculate IC50 values. For cell cycle and apoptosis, G401 and RD cells are plated in 15-cm dishes in duplicate at a density of 1 × 106 cells per plate. Cells are incubated with EPZ-6438 at 1 µM, in a total of 25 mL, over a course of 14 d, with cells being split back to original plating density on day 4, 7, and 11. Cell cycle analysis and TUNEL assay are performed using a Guava flow cytometer, following the manufacturer’s protocol. |
Animal Study: [1]
| Animal Models | SCID mice bearing s.c. G401 xenografts. |
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| Dosages | ~500 mg/kg |
| Administration | Oral administration |
References
Chemical Information
| Molecular Weight (MW) | 572.74 |
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| Formula | C34H44N4O4 |
| CAS No. | 1403254-99-8 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | E7438 |
| Solubility (25°C) * | In vitro | DMSO | 29 mg/mL (50 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | <1 mg/mL (<1 mM) | ||
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | [1,1’-Biphenyl]-3-carboxamide, N-[(1,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-4-methyl-4’-(4-morpholinylmethyl)- |
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