Tazemetostat Chemical Properties

Melting point:

>162°C (dec.)

Boiling point:

750.8±60.0 °C(Predicted)

Density 

1.163±0.06 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (up to at least 25 mg/ml).

pka

11.92±0.10(Predicted)

form 

solid

color 

Off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.

InChIKey

NSQSAUGJQHDYNO-UHFFFAOYSA-N

SMILES

C1(C2=CC=C(CN3CCOCC3)C=C2)=CC(N(CC)C2CCOCC2)=C(C)C(C(NCC2=C(C)C=C(C)NC2=O)=O)=C1

Tazemetostat Usage And Synthesis

Description

Tazemetostat (1403254-99-8) is a potent (Ki = 2.5nM wild type human PRC2-containing) and selective SAM-competitive inhibitor of the lysine methyltransferase EZH2.1?Tazemetostat displayed strong antiproliferative effects against SMARCB1-deleted malignant rhabdoid tumor (MRT) cell lines?in vitro. This antitumor activity was also observed in SMARTCB1 mutant mouse xenografts. It displayed potent antitumor activity in various cancer models including non-Hodgkins lymphoma2, pediatric glioma3, small-cell carcinoma of the ovary4, and synovial sarcomas5. Tazemetostat has also been shown to control inflammatory genes by modulating IRF1, IRF8, and STAT1 levels suggesting therapeutic potential for the treatment of neuroinflammatory diseases associated with microglial activation.6

Uses

EPZ 6438 is a potent and selective inhibitor of EZH2.

Biological Activity

Tazemetostat (EPZ-6438) 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 HMT.

Mechanism of action

Tazemetostat is an EZH2 inhibitor that can inhibit wild-type and certain gain-of-function mutations (such as Y646X, A687V, etc.) of EZH2. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), responsible for catalyzing the mono-, di-, and tri-methylation of lysine 27 at histone H3, leading to gene transcription inhibition. Tazemetostat inhibits the activity of EZH2 and reduces the tri-methylation of H3K27, thereby relieving the inhibition of certain tumor suppressor genes and exerting an anti-tumor effect.

Synthesis

Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholino-methyl)-[1,1'-biphenyl]-3-carboxamide. To a stirred mixed solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/water (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by Na2CO3 (11.2 g, 106.1 mmol). The reaction system was replaced with argon for 15 min, then Pd(PPh3)4 (3.40 g, 2.94 mmol) was added and again replaced with argon for 10 min. The reaction mixture was heated to 100 °C reaction. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM solvent mixture. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (100-200 mesh) with methanol:DCM as eluent to afford the target compound (Cas:1403254-99-8) as solid (12 g, 71%). Analytical data: LCMS: 573.35 (M+1)+; HPLC purity: 99.5% (254 nm) (retention time: 3.999 min; Methods: Column: YMC ODS-A 150 mm×4.6 mm×5 μm; Mobile phase: A: 0.05% TFA aqueous solution/B: 0.05% TFA acetonitrile solution; Injection volume: 10 μL; Column temperature: 30°C; Flow rate: 1.4 mL/min; Gradient: phase B increased from 5% to 95% in 5 min, held for 8 min, decreased to 5% in 1.5 min, and held at 5% for 9.51-12 min); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=), 7.2Hz), 7.57 (d, 2H, J=). 7.2 Hz), 7.36-7.39 (m,3H), 7.21 (s,1H), 5.85 (s,1H), 4.28 (d,2H,J=2.8 Hz), 3.82 (d,2H,J=9.6 Hz), 3.57 (bs,4H), 3.48 (s,2H), 3.24 (t,2H,J=10.8 Hz), 3.07 -3.09 (m,2H), 3.01 (m,1H), 2.36 (m,4H), 2.24 (s,3H), 2.20 (s,3H), 2.10 (s,3H), 1.64-1.67 (m,2H), 1.51-1.53 (m,2H), 0.83 (t,3H,J=6.4Hz).

in vivo

target

EZH2(Cell-free assay)

IC 50

EZH2

References

[1] SARAH K KNUTSON. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2013: 7922-7927. DOI:10.1073/pnas.1303800110
[2] SARAH K KNUTSON. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma.[J]. Molecular Cancer Therapeutics, 2014, 13 4: 842-854. DOI:10.1158/1535-7163.mct-13-0773
[3] FAIZAAN MOHAMMAD. EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas[J]. Nature Medicine, 2017, 23 4: 483-492. DOI:10.1038/nm.4293
[4] ELAYNE CHAN-PENEBRE. Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models.[J]. Molecular Cancer Therapeutics, 2017, 16 5: 850-860. DOI:10.1158/1535-7163.mct-16-0678
[5] SATOSHI KAWANO. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.[J]. PLoS ONE, 2016: e0158888. DOI:10.1371/journal.pone.0158888
[6] SARDER ARIFUZZAMAN . Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation[J]. Biochemical pharmacology, 2017, 137: Pages 61-80. DOI:10.1016/j.bcp.2017.04.016

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