Animal experiment:

Mice[1]Male C57BL/6-albino (B6(Cg)-Tyrc-2J/J) mice are injected intravenously with 100,000 EMRK1184 cells transfected with a luciferase-expression construct. Lymphoma growth is monitored. Three days after the lymphomacell transplant, all mice show luciferase activity, which indicate the expansion of lymphoma cells. Mice are then divided randomly into WM-1119-treatment with different conentrations (1, 2.5, 5, 10 μM) and vehicle-control groups. Because WM-1119 is rapidly cleared after intraperitoneal injection, with the plasma concentration decreasing to below 1 μM after 4-6 h cohorts of mice are injected every 8 h (three times per day, two cohorts of three mice per treatment group) or every 6 h (four times per day, two cohorts of three and six mice per treatment group)[1].

Target: lysine acetyltransferases, KAT6A(MOZ), KAT6B(MORF/QKF)

WM-1119 induces cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice

Data:

Treatment with WM-1119 arrests lymphoma growth.

Growth inhibition assays of Eμ-Myc lymphoma cell line EMRK1184 treated with WM-1119 and WM-8014 at the doses indicated.

KD(KAT6A)=0.002μM KD(KAT5) = 2.2μM KD(KAT7) = 0.5 μM

References

1. Baell JB, et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018 Aug;560(7717):253-257.