SGC0946

SGC0946 is an inhibitor of the non-SET domain-containing methyltransferase DOT1L (IC₅₀ = 0.3 nM).¹ It is selective for DOT1L over a panel of 12 additional protein methyltransferases, DNA methyltransferase 1 (DNMT1), and a panel of 29 receptors and ion channels. SGC0946 reduces the levels of dimethylated lysine 79 on histone 3 (H3K79me2) in MCF-10A breast cancer cells (IC₅₀ = 8.8 nM). It selectively reduces the viability of isolated human cord blood cells transformed with an MLL-AF9 fusion oncogene over those transformed with a TLS-ERG fusion oncogene when used at concentrations of 1 and 5 µM. Adoptive transfer of isolated human CD3⁺ T cells pre-incubated with SGC0946 (0.5 µM) prevents weight loss, increases survival, and reduces hepatic and colonic lymphocyte infiltration in a xenogeneic mouse model of graft versus host disease (GVHD).² See the Structural Genomics Consortium (SGC) website for more information.

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1. Yu, W., Chory, E.J., Wernimont, A.K., et al. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat. Commun. 3, 1288 (2012).

2. Kagoya, Y., Nakatsugawa, M., Saso, K., et al. DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models. Nat. Commun. 9(1), 1915 (2018).