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.