Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.
Identifieur interne : 003073 ( PubMed/Corpus ); précédent : 003072; suivant : 003074Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.
Auteurs : Nicholas A. Malmquist ; Sandeep Sundriyal ; Joachim Caron ; Patty Chen ; Benoit Witkowski ; Didier Menard ; Rossarin Suwanarusk ; Laurent Renia ; Francois Nosten ; María Belén Jiménez-Díaz ; I Igo 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 ScherfSource :
- Antimicrobial agents and chemotherapy [ 1098-6596 ] ; 2015.
English descriptors
- KwdEn :
- Animals, Antimalarials (chemistry), Antimalarials (therapeutic use), Azepines (chemistry), Azepines (therapeutic use), Female, Hep G2 Cells, Histone-Lysine N-Methyltransferase (antagonists & inhibitors), Humans, Malaria (drug therapy), Malaria, Falciparum (drug therapy), Mice, Mice, SCID, Plasmodium berghei (drug effects), Plasmodium berghei (pathogenicity), Plasmodium falciparum (drug effects), Plasmodium falciparum (pathogenicity), Quinazolines (chemistry), Quinazolines (therapeutic use).
- MESH :
- chemical , antagonists & inhibitors : Histone-Lysine N-Methyltransferase.
- chemical , chemistry : Antimalarials, Azepines, Quinazolines.
- chemical , therapeutic use : Antimalarials, Azepines, Quinazolines.
- drug effects : Plasmodium berghei, Plasmodium falciparum.
- drug therapy : Malaria, Malaria, Falciparum.
- pathogenicity : Plasmodium berghei, Plasmodium falciparum.
- Animals, Female, Hep G2 Cells, Humans, Mice, Mice, SCID.
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.
DOI: 10.1128/AAC.04419-14
PubMed: 25421480
Links to Exploration step
pubmed:25421480Le document en format XML
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<author><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A" last="Malmquist">Nicholas A. Malmquist</name>
<affiliation><nlm: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.</nlm:affiliation>
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<author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name>
<affiliation><nlm:affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</nlm:affiliation>
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<author><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name>
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<author><name sortKey="Jimenez Diaz, Maria Belen" sort="Jimenez Diaz, Maria Belen" uniqKey="Jimenez Diaz M" first="María Belén" last="Jiménez-Díaz">María Belén Jiménez-Díaz</name>
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<author><name sortKey="Angulo Barturen, I Igo" sort="Angulo Barturen, I Igo" uniqKey="Angulo Barturen I" first="I Igo" last="Angulo-Barturen">I Igo Angulo-Barturen</name>
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<author><name sortKey="Santos Martinez, Maria" sort="Santos Martinez, Maria" uniqKey="Santos Martinez M" first="María" last="Santos Martínez">María Santos Martínez</name>
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<author><name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
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<author><name sortKey="Sanz, Laura M" sort="Sanz, Laura M" uniqKey="Sanz L" first="Laura M" last="Sanz">Laura M. Sanz</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
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<author><name sortKey="Gamo, Francisco Javier" sort="Gamo, Francisco Javier" uniqKey="Gamo F" first="Francisco-Javier" last="Gamo">Francisco-Javier Gamo</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
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<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation><nlm:affiliation>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
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<author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name>
<affiliation><nlm:affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</nlm:affiliation>
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<author><name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<affiliation><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J" last="Delves">Michael J. Delves</name>
<affiliation><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Sinden, Robert E" sort="Sinden, Robert E" uniqKey="Sinden R" first="Robert E" last="Sinden">Robert E. Sinden</name>
<affiliation><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J" last="Fuchter">Matthew J. Fuchter</name>
<affiliation><nlm:affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
<affiliation><nlm: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.</nlm:affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.</title>
<author><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A" last="Malmquist">Nicholas A. Malmquist</name>
<affiliation><nlm: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.</nlm:affiliation>
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<author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name>
<affiliation><nlm:affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name>
<affiliation><nlm:affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name>
<affiliation><nlm: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.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Witkowski, Benoit" sort="Witkowski, Benoit" uniqKey="Witkowski B" first="Benoit" last="Witkowski">Benoit Witkowski</name>
<affiliation><nlm:affiliation>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Menard, Didier" sort="Menard, Didier" uniqKey="Menard D" first="Didier" last="Menard">Didier Menard</name>
<affiliation><nlm:affiliation>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Suwanarusk, Rossarin" sort="Suwanarusk, Rossarin" uniqKey="Suwanarusk R" first="Rossarin" last="Suwanarusk">Rossarin Suwanarusk</name>
<affiliation><nlm:affiliation>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name>
<affiliation><nlm:affiliation>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</name>
<affiliation><nlm: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.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Jimenez Diaz, Maria Belen" sort="Jimenez Diaz, Maria Belen" uniqKey="Jimenez Diaz M" first="María Belén" last="Jiménez-Díaz">María Belén Jiménez-Díaz</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Angulo Barturen, I Igo" sort="Angulo Barturen, I Igo" uniqKey="Angulo Barturen I" first="I Igo" last="Angulo-Barturen">I Igo Angulo-Barturen</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Santos Martinez, Maria" sort="Santos Martinez, Maria" uniqKey="Santos Martinez M" first="María" last="Santos Martínez">María Santos Martínez</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Sanz, Laura M" sort="Sanz, Laura M" uniqKey="Sanz L" first="Laura M" last="Sanz">Laura M. Sanz</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Gamo, Francisco Javier" sort="Gamo, Francisco Javier" uniqKey="Gamo F" first="Francisco-Javier" last="Gamo">Francisco-Javier Gamo</name>
<affiliation><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation><nlm:affiliation>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
<affiliation><nlm:affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name>
<affiliation><nlm:affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<affiliation><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
</affiliation>
</author>
<author><name sortKey="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J" last="Delves">Michael J. Delves</name>
<affiliation><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
</affiliation>
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<author><name sortKey="Sinden, Robert E" sort="Sinden, Robert E" uniqKey="Sinden R" first="Robert E" last="Sinden">Robert E. Sinden</name>
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</affiliation>
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<author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J" last="Fuchter">Matthew J. Fuchter</name>
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</affiliation>
</author>
<author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
<affiliation><nlm: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.</nlm:affiliation>
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<term>Azepines (therapeutic use)</term>
<term>Female</term>
<term>Hep G2 Cells</term>
<term>Histone-Lysine N-Methyltransferase (antagonists & inhibitors)</term>
<term>Humans</term>
<term>Malaria (drug therapy)</term>
<term>Malaria, Falciparum (drug therapy)</term>
<term>Mice</term>
<term>Mice, SCID</term>
<term>Plasmodium berghei (drug effects)</term>
<term>Plasmodium berghei (pathogenicity)</term>
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<term>Plasmodium falciparum (pathogenicity)</term>
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<term>Quinazolines (therapeutic use)</term>
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<term>Quinazolines</term>
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<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antimalarials</term>
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<term>Quinazolines</term>
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<term>Plasmodium falciparum</term>
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
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<Month>01</Month>
<Day>28</Day>
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<DateCompleted><Year>2015</Year>
<Month>10</Month>
<Day>08</Day>
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<Title>Antimicrobial agents and chemotherapy</Title>
<ISOAbbreviation>Antimicrob. Agents Chemother.</ISOAbbreviation>
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<ELocationID EIdType="doi" ValidYN="Y">10.1128/AAC.04419-14</ELocationID>
<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Malmquist</LastName>
<ForeName>Nicholas A</ForeName>
<Initials>NA</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0003-2822-8245</Identifier>
<AffiliationInfo><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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sundriyal</LastName>
<ForeName>Sandeep</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Caron</LastName>
<ForeName>Joachim</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chen</LastName>
<ForeName>Patty</ForeName>
<Initials>P</Initials>
<AffiliationInfo><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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Witkowski</LastName>
<ForeName>Benoit</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Menard</LastName>
<ForeName>Didier</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Suwanarusk</LastName>
<ForeName>Rossarin</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Renia</LastName>
<ForeName>Laurent</ForeName>
<Initials>L</Initials>
<AffiliationInfo><Affiliation>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nosten</LastName>
<ForeName>Francois</ForeName>
<Initials>F</Initials>
<AffiliationInfo><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.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Jiménez-Díaz</LastName>
<ForeName>María Belén</ForeName>
<Initials>MB</Initials>
<AffiliationInfo><Affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Angulo-Barturen</LastName>
<ForeName>Iñigo</ForeName>
<Initials>I</Initials>
<AffiliationInfo><Affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Santos Martínez</LastName>
<ForeName>María</ForeName>
<Initials>M</Initials>
<AffiliationInfo><Affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ferrer</LastName>
<ForeName>Santiago</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sanz</LastName>
<ForeName>Laura M</ForeName>
<Initials>LM</Initials>
<AffiliationInfo><Affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gamo</LastName>
<ForeName>Francisco-Javier</ForeName>
<Initials>FJ</Initials>
<AffiliationInfo><Affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wittlin</LastName>
<ForeName>Sergio</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Duffy</LastName>
<ForeName>Sandra</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Avery</LastName>
<ForeName>Vicky M</ForeName>
<Initials>VM</Initials>
<AffiliationInfo><Affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ruecker</LastName>
<ForeName>Andrea</ForeName>
<Initials>A</Initials>
<AffiliationInfo><Affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Delves</LastName>
<ForeName>Michael J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Sinden</LastName>
<ForeName>Robert E</ForeName>
<Initials>RE</Initials>
<AffiliationInfo><Affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Fuchter</LastName>
<ForeName>Matthew J</ForeName>
<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Scherf</LastName>
<ForeName>Artur</ForeName>
<Initials>A</Initials>
<AffiliationInfo><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.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2014</Year>
<Month>11</Month>
<Day>24</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>United States</Country>
<MedlineTA>Antimicrob Agents Chemother</MedlineTA>
<NlmUniqueID>0315061</NlmUniqueID>
<ISSNLinking>0066-4804</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000962">Antimalarials</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D001381">Azepines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C518299">BIX 01294</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011799">Quinazolines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.1.1.-</RegistryNumber>
<NameOfSubstance UI="C021362">histone methyltransferase</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.1.1.43</RegistryNumber>
<NameOfSubstance UI="D011495">Histone-Lysine N-Methyltransferase</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000962" MajorTopicYN="N">Antimalarials</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D001381" MajorTopicYN="N">Azepines</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D056945" MajorTopicYN="N">Hep G2 Cells</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011495" MajorTopicYN="N">Histone-Lysine N-Methyltransferase</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008288" MajorTopicYN="N">Malaria</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D016778" MajorTopicYN="N">Malaria, Falciparum</DescriptorName>
<QualifierName UI="Q000188" MajorTopicYN="N">drug therapy</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D016513" MajorTopicYN="N">Mice, SCID</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010962" MajorTopicYN="N">Plasmodium berghei</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000472" MajorTopicYN="N">pathogenicity</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D010963" MajorTopicYN="N">Plasmodium falciparum</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
<QualifierName UI="Q000472" MajorTopicYN="N">pathogenicity</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011799" MajorTopicYN="N">Quinazolines</DescriptorName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
</MeshHeading>
</MeshHeadingList>
<OtherID Source="NLM">PMC4335868</OtherID>
</MedlineCitation>
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<Month>11</Month>
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<Hour>6</Hour>
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<PubMedPubDate PubStatus="pubmed"><Year>2014</Year>
<Month>11</Month>
<Day>26</Day>
<Hour>6</Hour>
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<PubMedPubDate PubStatus="medline"><Year>2015</Year>
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<Hour>6</Hour>
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<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">25421480</ArticleId>
<ArticleId IdType="pii">AAC.04419-14</ArticleId>
<ArticleId IdType="doi">10.1128/AAC.04419-14</ArticleId>
<ArticleId IdType="pmc">PMC4335868</ArticleId>
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