Our basic research on virulence gene control revealed that epigenetic factors such as histone methylation control antigenic variation but also the developmental progression of malaria parasites during the complex life cycle in the human host (Lopez-Rubio et al., 2009 Cell Host & Microbe). We hypothesized that this epigenetic mechanism could be a novel target that could block the immune evasion process and interfere with parasite development in general, depending on the inhibition of the histone methylation site. We investigated P. falciparum histone lysine methyltransferases (HKMT) as a potential target class for the development of novel antimalarials. In collaboration with Matt Fuchter (medicinal chemist, Imperial College London) who synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds (BIX-01294 and TM2-115) inhibit malaria parasite HKMTs, resulting in rapid and irreversible parasite death. Our data position HKMTs 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 (Malmquist et al., 2012 PNAS). We are now exploring the potential of the BIX compound libraries (>150 compounds) to specifically interfere with var gene repression via H3K9 methylation. More recently, we initiated a collaboration with Prof. Mazier (UPMC/INSERM UMR 945) to exploit the BIX compound on liver dormant stages (hypnozoites). The Mazier laboratory has developed a ground-breaking protocol for long-term in vitro cultivation of P. cynomolgi-infected primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation (Dembele et al., 2014 Nature Medicine).