Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans
Malmquist NA., Sundriyal S., Caron J., Chen P., Witkowski B., Menard D., Suwanarusk R., Renia L., Nosten F., Jiménez-Díaz MB., Angulo-Barturen I., Martínez MS., Ferrer S., Sanz LM., Gamo F-J., Wittlin S., Duffy S., Avery VM., Ruecker A., Delves MJ., Sinden RE., Fuchter MJ., Scherf A.
<jats:title>ABSTRACT</jats:title><jats:p>Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising<jats:italic>in vitro</jats:italic>parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for<jats:italic>in vitro</jats:italic>and<jats:italic>in vivo</jats:italic>efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent<jats:italic>in vitro</jats:italic>activity, with 50% inhibitory concentrations (IC<jats:sub>50</jats:sub>s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>isolates. Activities against<jats:italic>ex vivo</jats:italic>clinical isolates of both<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium vivax</jats:named-content>were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in<jats:italic>in vivo</jats:italic>mouse models of<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium berghei</jats:named-content>and<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.</jats:p>