title: Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.
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 50% inhibitory concentrations (IC50s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax 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 in vivo mouse models of Plasmodium berghei and P. falciparum 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.
authors.affiliation: Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France nicholas.malmquist@pasteur.fr artur.scherf@pasteur.fr.
authors.forename: Nicholas A
authors.identifier: http://orcid.org/0000-0003-2822-8245
authors.initials: NA
authors.lastname: Malmquist
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sundriyal
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.
authors.forename: Joachim
authors.initials: J
authors.lastname: Caron
authors.affiliation: Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France.
authors.forename: Patty
authors.initials: P
authors.lastname: Chen
authors.affiliation: Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Benoit
authors.initials: B
authors.lastname: Witkowski
authors.affiliation: Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Rossarin
authors.initials: R
authors.lastname: Suwanarusk
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.affiliation: Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand.
authors.forename: Francois
authors.initials: F
authors.lastname: Nosten
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Santos Martínez
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruecker
authors.affiliation: Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delves
authors.affiliation: Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Sinden
authors.affiliation: Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fuchter
authors.affiliation: Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France nicholas.malmquist@pasteur.fr artur.scherf@pasteur.fr.
authors.forename: Artur
authors.initials: A
authors.lastname: Scherf
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000627:therapeutic use*; D001381:Azepines / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D056945:Hep G2 Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D010962:Plasmodium berghei / Q000187:drug effects / Q000472:pathogenicity; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity; D011799:Quinazolines / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D001381:Azepines; C518299:BIX 01294; D011799:Quinazolines; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase