1403254-99-8

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

EPZ 6438 is a potent and selective inhibitor of EZH2.

Tazemetostat (EPZ-6438) is a first-in-class, selective, oral inhib itor of histone methyltransferase enhancer of zeste homolog 2 (EZH2) approved by the U.S. Food and Drug Administration (FDA) for the treatment of EZH2 mutant (EZH2 mut) relapsed or refractory FL in patients who have received two or more prior systemic therapies and in those with relapsed or refractory FL who have no satisfactory alternative treatment options^[7]. In addition, a Phase II clinical trial is currently underway to investigate the use of Tazemetostat for the treatment of recurrent ovarian or endometrial cancer.

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.

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.

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).

EZH2(Cell-free assay)

EZH2

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