SGC0946 (trifluoroacetate salt)

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 ?M. Adoptive transfer of isolated human CD3⁺ T cells pre-incubated with SGC0946 (0.5 ?M) prevents weight loss, increases survival, and reduces hepatic and colonic lymphocyte infiltration in a xenogeneic mouse model of graft versus host disease (GVHD).²

References:
[1]. Yu, W., Chory, E.J., Wernimont, A.K., et al.Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitorsNat. Commun.31288(2012).
[2]. Kagoya, Y., Nakatsugawa, M., Saso, K., et al.DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy modelsNat. Commun.9(1)1915(2018).