TazemetoSTAT 是一种口服的、小分子选择性和 S-腺苷甲硫氨酸 (SAM) 竞争性组蛋白甲基转移酶 EZH2 抑制剂，具有潜在的抗肿瘤活性。它抑制含有 PRC2 复合体的野生型 EZH2 的活性，Ki值为 2.5±0.5 nM。它抑制 EZH2，在肽测定和核小体测定中 IC50分别为 11 和 16 nM。它还抑制 EZH1和大鼠 EZH2，IC50分别为 392 和 4 nM。

Tazemetostat is an orally available, small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of histone methyltransferase EZH2, with potential antineoplastic activity. Upon oral administration, Tazemetostat selectively inhibits the activity of both wild-type and mutated forms of EZH2. Inhibition of EZH2 specifically prevents the methylation of histone H3 lysine 27 (H3K27).

在G401异种移植物的SCID小鼠体内,皮下注射EPZ-6438会造成肿瘤郁积,且在给药期间,会使肿瘤生长显著延迟,但对体重影响较小.

EPZ-6438抑制神经元分化的基因表达和细胞周期,同时抑制刺猬的通路基因（MYC和EZH2）。在几种EZH2突变体淋巴瘤细胞中,氢化泼尼松或地塞米松可增强EPZ-6438的抗增殖作用。EPZ-6438使野生型或SMARCB1突变细胞中总体H3K27Me3水平出现浓度依赖性降低,且对MRT细胞系（去除SMARCB1）有较强的抗增殖作用（IC50：32 nM-1000 nM）。

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.

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.(Only for Reference)

1403254-99-8

C34H44N4O4

572.74

EPZ6438;E-7438

Ethanol:<1 mgml
H2O:<1 mgml
DMSO:33 mg/mL(57.6 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years