Epigenetic factors such as histone methylation control the developmental 
progression of malaria parasites during the complex life cycle in the human 
host. We investigated Plasmodium falciparum histone lysine methyltransferases as 
a potential target class for the development of novel antimalarials. We 
synthesized a compound library based upon a known specific inhibitor (BIX-01294) 
of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its 
derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC(50) 
values of ~100 nM, values at least 22-fold more potent than their apparent 
IC(50) toward two human cell lines and one mouse cell line. These compounds 
irreversibly arrested parasite growth at all stages of the intraerythrocytic 
life cycle. Decrease in parasite viability (>40%) was seen after a 3-h 
incubation with 1 µM BIX-01294 and resulted in complete parasite killing after a 
12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain 
infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced 
parasitemia the following day. Importantly, treatment of P. falciparum parasites 
in culture with BIX-01294 or TM2-115 resulted in significant reductions in 
histone H3K4me3 levels in a concentration-dependent and exposure time-dependent 
manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit 
malaria parasite histone methyltransferases, resulting in rapid and irreversible 
parasite death. Our data position histone lysine methyltransferases as a 
previously unrecognized target class, and BIX-01294 as a promising lead 
compound, in a presently unexploited avenue for antimalarial drug discovery 
targeting multiple life-cycle stages.