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.
target
EZH2(Cell-free assay)
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
