GSK126

GSK126 is an inhibitor of the histone-lysine methyltransferase enhancer of zest homolog 2 (EZH2; IC₅₀ = 9.9 nM).¹ It is selective for EZH2 over EZH1 (IC₅₀ = 680 nM) and a variety of SET-domain-containing and non-SET-domain-containing methyltransferases (IC₅₀s = 13->100 µM). GSK126 (7-252 nM) reduces global trimethylation of lysine 27 on histone H3 (H3K27me3) in a variety of diffuse large B cell lymphoma (DLCBL) cells expressing wild-type or mutant EZH2. It also reduces tumor growth in a Pfeiffer DLBCL mouse xenograft model when administered at a dose of 50 mg/kg per day. GSK126 (10 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.² It also reduces H3K27me3 levels and induces insulin secretion and glucose-stimulated insulin secretion in primary human pancreatic ductal epithelial cells.

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1. McCabe, M.T., Ott, H.M., Ganji, G., et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492(7427), 108-112 (2012).

2. 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).

Witt, A.E., Lee, C.-W., Lee, T.I., et al. Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer. Oncogene 36(12), 1707-1720 (2017).