Publication:
Histone methyltransferase inhibitors are orally bioavailable, fast- Acting molecules with activity against different species causing malaria in humans

Issued Date

2015-02-01

Resource Type

Article

ISSN

10986596
00664804

DOI

10.1128/AAC.04419-14

Other identifier(s)

2-s2.0-84921917278

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Antimicrobial Agents and Chemotherapy. Vol.59, No.2 (2015), 950-959

Suggested Citation

Nicholas A. Malmquist, Sandeep Sundriyal, Joachim Caron, Patty Chen, Benoit Witkowski, Didier Menard, Rossarin Suwanarusk, Laurent Renia, Francois Nosten, María Belén Jiménez-Díaz, Iñigo Angulo-Barturen, María Santos Martínez, Santiago Ferrer, Laura M. Sanz, Francisco Javier Gamo, Sergio Wittlin, Sandra Duffy, Vicky M. Avery, Andrea Ruecker, Michael J. Delves, Robert E. Sinden, Matthew J. Fuchter, Artur Scherf Histone methyltransferase inhibitors are orally bioavailable, fast- Acting molecules with activity against different species causing malaria in humans. Antimicrobial Agents and Chemotherapy. Vol.59, No.2 (2015), 950-959. doi:10.1128/AAC.04419-14 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/36520

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Title

Histone methyltransferase inhibitors are orally bioavailable, fast- Acting molecules with activity against different species causing malaria in humans

Author(s)

Nicholas A. Malmquist
 Sandeep Sundriyal
 Joachim Caron
 Patty Chen
 Benoit Witkowski
 Didier Menard
 Rossarin Suwanarusk
 Laurent Renia
 Francois Nosten
 María Belén Jiménez-Díaz
 Iñigo Angulo-Barturen
 María Santos Martínez
 Santiago Ferrer
 Laura M. Sanz
 Francisco Javier Gamo
 Sergio Wittlin
 Sandra Duffy
 Vicky M. Avery
 Andrea Ruecker
 Michael J. Delves
 Robert E. Sinden
 Matthew J. Fuchter
 Artur Scherf

Other Contributor(s)

Institut Pasteur, Paris
 CNRS Centre National de la Recherche Scientifique
 Imperial College London
 Institut Pasteur du Cambodge
 Agency for Science, Technology and Research, Singapore
 Nuffield Department of Clinical Medicine
 Mahidol University
 GlaxoSmithKline plc, Spain
 Swiss Tropical and Public Health Institute (Swiss TPH)
 Universitat Basel
 Griffith University

Abstract

©2015 American Society for Microbiology. 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 (IC<inf>50</inf>s) 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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/36520

Collections

Scopus 2011-2015