EPZ6438

EPZ6438 is an inhibitor of the histone-lysine methyltransferase enhancer of zeste homolog 2 (EZH2; IC₅₀ = 11 nM).¹ It also inhibits EZH2 containing a variety of mutations, including EZH2^A677G, EZH2^A687V, EZH2^Y641F, and EZH2^Y641S (IC₅₀s = 2, 2, 14, and 4 nM, respectively). It is selective for wild-type and mutant EZH2 over EZH1 (IC₅₀ = 392 nM) and a variety of other histone methyltransferases (IC₅₀s = >50 or >100 µM for all). EPZ6438 reduces trimethylation of lysine 27 on histone H3 (H3K27me3) in various lymphoma cells expressing wild-type or mutant EZH2 (IC₅₀s = 2-8 and 2-22 nM, respectively) and inhibits proliferation of the same cells (IC₅₀s = 99-6,200 and 0.49-5,800 nM, respectively).² EPZ6438 (1 µM) induces insulin production and glucose-stimulated insulin secretion in human pancreatic exocrine cells isolated from juvenile patients with type 1 diabetes or adults without diabetes.³ It also reduces H3K27me3 levels and induces insulin secretion and glucose-stimulated insulin secretion in human pancreatic ductal epithelial cells in vitro. Formulations containing EPZ6438 have been used in the treatment of relapsed or refractory follicular lymphoma.

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1. Knutson, S.K., Warholic, N.M., Wigle, T.J., et al. Durable tumor regression in genetically altered malignant rhabdoid tumors by inhibition of methyltransferase EZH2. Proc. Natl. Acad. Sci. USA 110(19), 7922-7927 (2013).

2. Knutson, S.K., Kawano, S., Minoshima, Y., et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13(4), 842-854 (2014).

3. Al-Hasani, K., Marikar, S.N., Kaipananickal, H., et al. EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors. Signal Transduct. Target Ther. 9(1), 2 (2024).