Tazemetostat | EZH2 inhibitor

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

References/Citations:

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