Tazemetostat (EPZ-6438)

製品コードS7128 バッチS712815

化学情報

	Synonyms	E7438	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₃₄H₄₄N₄O₄
	分子量	572.74	CAS No.	1403254-99-8
Solubility (25°C)*	体外	DMSO	100 mg/mL warmed with 50ºC water bath (174.59 mM)
		Water	Insoluble
		Ethanol	Insoluble
* <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.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	Tazemetostat (EPZ-6438, E7438) is a potent, and selective EZH2 inhibitor with K_i and IC50 of 2.5 nM and 11 nM in cell-free assays, exhibiting a 35-fold selectivity versus EZH1 and >4,500-fold selectivity relative to 14 other HMTs.
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]
特徴	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.

プロトコル(参考用のみ)

キナーゼアッセイ	Biochemical Methods
キナーゼアッセイ	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.
細胞アッセイ	細胞株	Mutant cell lines (G401, A204, G402, KYM-1), Wild type cell line (RD, 293, SJCRH30)
	濃度	~10 μM
	反応時間	7 days
	実験の流れ	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.
動物実験	動物モデル	SCID mice bearing s.c. G401 xenografts.
	投薬量	~500 mg/kg
	投与方法	Oral administration

参考

カスタマーフィードバック

: Data from [Data independently produced by , , Cell, 2018, 175(1):186-199]

: Data from [Data independently produced by , , J Pathol, 2017, 242(3):371-383]

: Data from [Data independently produced by , , Clin Epigenetics, 2018, 10(1):121]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors [ Signal Transduct Target Ther, 2024, 9(1):2]	PubMed: 38161208
Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma [ Nat Commun, 2024, 15(1):1367]	PubMed: 38355622
C-terminal binding protein (CTBP2) is a novel tumor suppressor targeting the MYC-IRF4 axis in multiple myeloma [ Blood Adv, 2024, bloodadvances.2023010218]	PubMed: 38457926
Inhibition of epigenetic and cell cycle-related targets in glioblastoma cell lines reveals that onametostat reduces proliferation and viability in both normoxic and hypoxic conditions [ Sci Rep, 2024, 14(1):4303]	PubMed: 38383756
NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis [ bioRxiv, 2024, 2024.02.22.581560]	PubMed: 38464251
EZH2 mediated metabolic rewiring promotes tumor growth independently of histone methyltransferase activity in ovarian cancer [ Mol Cancer, 2023, 22(1):85]	PubMed: 37210576
PRC2.1- and PRC2.2-specific accessory proteins drive recruitment of different forms of canonical PRC1 [ Mol Cell, 2023, 83(9):1393-1411.e7]	PubMed: 37030288
EZH2 inhibition stimulates repetitive element expression and viral mimicry in resting splenic B cells [ EMBO J, 2023, 10.15252/embj.2023114462]	PubMed: 37934086
Polycomb repressor complex 2 suppresses interferon-responsive MHC-II expression in melanoma cells and is associated with anti-PD-1 resistance [ J Immunother Cancer, 2023, 11(11)e007736]	PubMed: 38315170
Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation [ Haematologica, 2023, 108(9):2487-2502]	PubMed: 37021526

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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