Histone methyltransferase inhibitors: orally bioavailable, fast acting molecules with activity against different human malaria species

Abstract

Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity with IC50 values <50 nM against drug sensitive laboratory strains and multi-drug resistant field isolates including artemisinin refractory P. falciparum isolates. Activity against ex vivo clinical isolates of both P. falciparum and P. vivax were similar with potencies of 300-400 nM. Sexual stage gametocyte inhibition occurs at micromolar levels, however, mature gametocyte progression to gamete formation is inhibited at sub-micromolar concentrations. Parasite reduction ratio analysis confirms a fast asexual stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of P. berghei and P. falciparum infection. The discovery of a rapid and broad-acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.