体外活性：EPZ-6438 浓度依赖性地降低野生型或 SMARCB1 突变细胞中的整体 H3K27Me3 水平，并在 SMARCB1 缺失的 MRT 细胞系中诱导强烈的抗增殖作用，IC50 范围为 32 nM 至 1000 nM。 EPZ-6438 诱导神经元分化和细胞周期抑制的基因表达，同时抑制 Hedgehog 通路基因 MYC 和 EZH2 的表达。在几种 EZH2 突变淋巴瘤细胞系中，泼尼松龙或地塞米松可增强 EPZ-6438 的抗增殖作用。激酶测定：EPZ-6438 在 1X 测定缓冲液（20 mM Bicine [pH 7.6]、0.002% Tween-20、每孔 40 μL 5 nM PRC2（50 μL 中的最终测定浓度为 4 nM）中孵育 30 分钟， 0.005% 牛皮明胶和 0.5 mM DTT）。每孔添加 10 μL 底物混合物，其中包含测定缓冲液 3 H-SAM、未标记的 SAM 和代表组蛋白 H3 残基 21-44 的肽（含有 C 端生物素（附加到 C 端酰胺封端的赖氨酸））以启动反应（两种底物以其各自的 Km 值存在于最终反应混合物中，这种测定形式称为“平衡条件”。针对每种酶指示了底物的最终浓度和底物肽的甲基化状态。反应孵育室温下 90 分钟，每孔加入 10 μL 600 μM 未标记 SAM，然后转移至 384 孔 flashplate，30 分钟后清洗。 细胞测定：对于贴壁细胞系增殖测定，每个细胞系的铺板密度为根据生长曲线（通过 ATP 含量测量）和 7 天时间过程中的密度确定。在化合物处理前一天，将细胞一式三份接种在 96 孔板中（第 0-7 天的时间过程）或6 孔板（用于在第 7 天重新接种以完成剩余的时间过程）。第 0 天，细胞未经处理、DMSO 处理或用 EPZ-6438 处理（从 10 µM 开始并以三倍或四倍稀释度逐渐减少）。使用 Cell Titer Glo 在第 0 天、第 4 天和第 7 天对板进行读数，并在第 4 天补充化合物/培养基。在第 7 天，将六孔板用胰蛋白酶消化、离心并重悬于新鲜培养基中，以便通过以下方法进行计数： Vi-细胞。将每次处理的细胞以原始密度重新接种到 96 孔板中，一式三份。让细胞在平板上粘附过夜，并按第 0 天处理细胞。在第 7、11 和 14 天，使用 Cell Titer Glo 读取平板，并在第 11 天补充化合物/培养基。一式三份的平均值为用于绘制随时间变化的增殖曲线，并计算 IC50 值。对于细胞周期和细胞凋亡，将 G401 和 RD 细胞以每板 1 × 106 个细胞的密度一式两份铺在 15 cm 培养皿中。将细胞与 1 µM 的 EPZ-6438（总共 25 mL）一起孵育 14 天，并在第 4、7 和 11 天将细胞分裂回原始铺板密度。细胞周期分析和 TUNEL 测定使用番石榴流式细胞仪按照制造商的方案进行。

在携带 sc G401 异种移植物的 SCID 小鼠中，EPZ-6438 在给药期间诱导肿瘤停滞，并产生显着的肿瘤生长延迟，而对体重的影响最小。

Absorption, Distribution and Excretion
Tazemetostat 800mg twice daily leads to a Cmax of 829ng/mL, with a Tmax of 1-2 hours , and an AUC of 3340ng\*h/mL. Absorption is not significantly affected by a high fat, high calorie meal. Tazemetostat is 33% bioavailable.
Tazemetostat is 15% eliminated in urine and 79% eliminated in feces.
Tazemetostat has a volume of distribution of 1230L.
Tazemetostat has an apparent total clearance of 274L/h.

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Metabolism / Metabolites
Tazemetostat is metabolized by CYP3A4 to an inactive desethyl metabolite and one other inactive metabolite not described.

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Biological Half-Life
Tazemetostat has a terminal elimination half life of 3.1h.

Hepatotoxicity
In clinical trials, serum ALT elevations occurred in 14% and AST elevations in 18% of patients on tazemetostat therapy and rose to more than 5 times ULN in 3.5%. Nevertheless, there were no instances of clinically apparent liver injury with symptoms or jaundice in several multicenter open-label trials of tazemetostat. Despite the frequency of adverse events during tazemetostat therapy, discontinuations due to adverse events are uncommon. Clinical experience with tazemetostat, however, is limited and the frequency of de novo serum enzyme elevations during treatment raises the issue of its potential for causing hepatotoxicity.
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Protein Binding
Tazemetostat is 88% protein bound in plasma.

[1]. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferaseEZH2. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7.

Tazemetostat is a methyltransferase inhibitor used to treat metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. Tazemetostat was first named in literature as EPZ-6438. Tazemetaostat was granted FDA approval on 23 January 2020.
Tazemetostat is a Methyltransferase Inhibitor. The mechanism of action of tazemetostat is as a Methyltransferase Inhibitor, and Multidrug and Toxin Extrusion Transporter 1 Inhibitor, and Multidrug and Toxin Extrusion Transporter 2 K Inhibitor.
Tazemetostat is a methyltransferase inhibitor and antineoplastic agent used in the therapy of advanced epithelioid sarcoma. Tazemetostat is associated with a moderate rate of transient serum enzyme elevations during therapy, but has not been implicated in cases of clinically apparent acute liver injury with jaundice.
Tazemetostat is an orally available, small molecule selective and S-adenosyl methionine (SAM) competitive inhibitor of histone methyl transferase 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). This decrease in histone methylation alters gene expression patterns associated with cancer pathways and results in decreased tumor cell proliferation in EZH2 mutated cancer cells. EZH2, which belongs to the class of histone methyltransferases (HMTs), is overexpressed or mutated in a variety of cancer cells and plays a key role in tumor cell proliferation.
See also: Tazemetostat Hydrobromide (active moiety of); Tazemetostat hydrochloride (is active moiety of); Tazemetostat dihydrobromide (is active moiety of) ... View More ...

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Drug Indication
Tazemetostat is indicated to treat adult and pediatric patients 16 years and older with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection. It is also indicated to treat adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an IZH2 mutation and who have received at least 2 prior systemic therapies. Additionally, it is indicated in adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options.

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Mechanism of Action
EZH2 is a methyltransferase subunit of the polycomb repressive complex 2 (PRC2) which catalyzes multiple methylations of lysine 27 on histone H3 (H3K27). Trimethylation of this lysine inhibits the transcription of genes associated with cell cycle arrest. PRC2 is antagonized by the switch/sucrose non-fermentable (SWI/SNF) multiprotein complex. Abnormal activation of EZH2 or loss of function mutations in SWI/SNF lead to hyper-trimethylation of H3K27. Hyper-trimethylation of H3K27 leads to cancer cell de-differentiation, a gain of cancer stem cell-like properties. De-differentiation can allow for cancer cell proliferation. Tazemetostat inhibits EZH2, preventing hyper-trimethylation of H3K27 and an uncontrollable cell cycle.

C34H44N4O4

572.74

572.336

1403254-99-8

1467052-84-1 (HCl);1467052-75-0 (HBr);1403254-99-8;

66558664

Off-white to light yellow solid powder

1.2±0.1 g/cm3

750.8±60.0 °C at 760 mmHg

407.9±32.9 °C

0.0±2.5 mmHg at 25°C

1.589

0.98

90.65

2

6

9

42

992

0

NSQSAUGJQHDYNO-UHFFFAOYSA-N

InChI=1S/C34H44N4O4/c1-5-38(29-10-14-41-15-11-29)32-20-28(27-8-6-26(7-9-27)22-37-12-16-42-17-13-37)19-30(25(32)4)33(39)35-21-31-23(2)18-24(3)36-34(31)40/h6-9,18-20,29H,5,10-17,21-22H2,1-4H3,(H,35,39)(H,36,40)

N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide

Tazemetostat; E7-438; EPZ 6438; E 7438; EPZ6438; tazerik; E7438; EPZ-6438;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)