1403254-99-8

Basic information

• Product Name: EPZ-6438
• Synonyms: EPZ-6438;E-7438;EPZ-7438;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)-[1,1'-biphenyl]-3-carboxamide;[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)-;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)-[1,1'-biphenyl]-3-carboxamide EPZ6438;E7438, Tazemetostat;Tazemetostat
• CAS NO: 1403254-99-8
• Molecular Formula: C₃₄H₄₄N₄O₄
• Molecular Weight: 572.73756
• Product Categories: Inhibitors
• Mol File: 1403254-99-8.mol
• Article Data: 6

Chemical Properties

• Boiling Point: 750.8±60.0 °C(Predicted)
• Appearance: /
• 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)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 1 month.
• CAS DataBase Reference: EPZ-6438(CAS DataBase Reference)
• NIST Chemistry Reference: EPZ-6438(1403254-99-8)
• EPA Substance Registry System: EPZ-6438(1403254-99-8)

Safety Data

• Hazardous Substances Data: 1403254-99-8(Hazardous Substances Data)

Usage

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.

References

1) Knutson?et al.?(2013),?Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2;?Proc. Natl. Acad. Sci. USA?110?7922 2) Knutson?et al.?(2014),?Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma; Mol.Cancer Ther.?13?842 3) Mohammad?et al. (2017),?EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas; Nat. Med.?23?483 4) Chan-Penebre?et al.?(2017),?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; Mol. Cancer Ther.?16?850 5) Kawano?et al.?(2016),?Preclinical Evidence of Anti-Tumor Activity by EZH2 Inhibition in Human Models of Synovial Sarcoma; PLoS One?11?e0158888 6) Arifuzzaman?et al.?(2017),?Selective inhibition of EZH2 by a small molecule inhibitor regulates microglial gene expression essential for inflammation; Biochem. Pharmacol.?137?61

Upstream product

• 29943-42-8 Tetrahydro-4H-pyran-4-one 
• 107650-20-4 5-bromo-2-methyl-3-nitro-benzoic acid 
• 1173081-96-3 (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methylamine hydrochloride 
• 769-28-8 2-hydroxy-4,6-dimethyl-3-carbonitrile 
• 771579-27-2 3-(aminomethyl)-4,6-dimethylpyridin-2-ol 
• 1403257-81-7 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl benzoic acid 
• 1403257-80-6 5-bromo-N-((4, 6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl) amino)-2-methylbenzamide 
• 364794-79-6 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine 
• 1403257-79-3 2-methyl-3-[ethyl(tetrahydro-2H-pyran-4-yl)amino]-5-bromobenzoic acid methyl ester 
• 1403257-49-7 2-methyl-3[(tetrahydro-2H-pyran-4-yl)amino]-5-bromobenzoic acid methyl ester 
• 1000342-11-9 2-methyl-3-amino-5-bromobenzoic acid methyl ester 
• 79669-49-1 5-bromo-2-methylbenzoic acid 
• 1975-50-4 2-methyl-3-nitrobenzic acid 
• 220514-28-3 5-bromo-2-methyl-3-nitrobenzoic acid methyl ester 

Downstream Products

• 1403256-09-6 N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-4,4'-dimethyl-[1,1'-biphenyl]-3-carboxamide 
• 1467052-75-0 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 hydrobromide 

Relevant articles and documents

The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat

Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.

HYDROCHLORIDE SALT FORM FOR EZH2 INHIBITION

Provided herein are novel solid forms of 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 hydrochloride, and related compositions and methods.

SALT FORM OF A HUMAN HI STONE METHYLTRANSF ERASE EZH2 INHIBITOR

Provided herein is 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 hydrobromide. Also provided herein is a particular polymorph form of this compo