AustralieFrV1, PubMed, Checkpoint, bibRecord, 002B12

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

Identifieur interne : 002B12 ( PubMed/Checkpoint ); précédent : 002B11; suivant : 002B13

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

Auteurs : Nicholas A. Malmquist [France] ; Sandeep Sundriyal [Royaume-Uni] ; Joachim Caron [Royaume-Uni] ; Patty Chen [France] ; Benoit Witkowski [Cambodge] ; Didier Menard [Cambodge] ; Rossarin Suwanarusk [Singapour] ; Laurent Renia [Singapour] ; Francois Nosten [Thaïlande] ; María Belén Jiménez-Díaz [Espagne] ; I Igo Angulo-Barturen [Espagne] ; María Santos Martínez [Espagne] ; Santiago Ferrer [Espagne] ; Laura M. Sanz [Espagne] ; Francisco-Javier Gamo [Espagne] ; Sergio Wittlin [Suisse] ; Sandra Duffy [Australie] ; Vicky M. Avery [Australie] ; Andrea Ruecker [Royaume-Uni] ; Michael J. Delves [Royaume-Uni] ; Robert E. Sinden [Royaume-Uni] ; Matthew J. Fuchter [Royaume-Uni] ; Artur Scherf [France]

Source :

Antimicrobial agents and chemotherapy [ 1098-6596 ] ; 2015.

RBID : pubmed:25421480

Descripteurs français

KwdFr :
- Animaux, Antipaludiques (), Antipaludiques (usage thérapeutique), Azépines (), Azépines (usage thérapeutique), Cellules HepG2, Femelle, Histone-lysine N-methyltransferase (antagonistes et inhibiteurs), Humains, Paludisme (traitement médicamenteux), Paludisme à Plasmodium falciparum (traitement médicamenteux), Plasmodium berghei (), Plasmodium berghei (pathogénicité), Plasmodium falciparum (), Plasmodium falciparum (pathogénicité), Quinazolines (), Quinazolines (usage thérapeutique), Souris, Souris SCID.
MESH :
- antagonistes et inhibiteurs : Histone-lysine N-methyltransferase.
- pathogénicité : Plasmodium berghei, Plasmodium falciparum.
- traitement médicamenteux : Paludisme, Paludisme à Plasmodium falciparum.
- usage thérapeutique : Antipaludiques, Azépines, Quinazolines.
- Animaux, Antipaludiques, Azépines, Cellules HepG2, Femelle, Humains, Plasmodium berghei, Plasmodium falciparum, Quinazolines, Souris, Souris SCID.

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

Affiliations:

Australie, Cambodge, Espagne, France, Royaume-Uni, Singapour, Suisse, Thaïlande
Angleterre, Communauté de Madrid, Grand Londres, Oxfordshire, Île-de-France
Londres, Madrid, Oxford, Paris
Université d'Oxford

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Le document en format XML

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<author><name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name>
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<author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</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="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>
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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>
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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>
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<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation wicri:level="1"><nlm:affiliation>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.</nlm:affiliation>
<country xml:lang="fr">Suisse</country>
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</affiliation>
</author>
<author><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
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</affiliation>
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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>
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<author><name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
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<author><name sortKey="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J" last="Delves">Michael J. Delves</name>
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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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<wicri:regionArea>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
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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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<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Chemistry, Imperial College London, South Kensington Campus, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
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<author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
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<region type="old region">Île-de-France</region>
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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>
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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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<wicri:regionArea>Department of Chemistry, Imperial College London, South Kensington Campus, London</wicri:regionArea>
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<author><name sortKey="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name>
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<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
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<author><name sortKey="Witkowski, Benoit" sort="Witkowski, Benoit" uniqKey="Witkowski B" first="Benoit" last="Witkowski">Benoit Witkowski</name>
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<country xml:lang="fr">Cambodge</country>
<wicri:regionArea>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh</wicri:regionArea>
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<author><name sortKey="Menard, Didier" sort="Menard, Didier" uniqKey="Menard D" first="Didier" last="Menard">Didier Menard</name>
<affiliation wicri:level="1"><nlm:affiliation>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia.</nlm:affiliation>
<country xml:lang="fr">Cambodge</country>
<wicri:regionArea>Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh</wicri:regionArea>
<wicri:noRegion>Phnom Penh</wicri:noRegion>
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<author><name sortKey="Suwanarusk, Rossarin" sort="Suwanarusk, Rossarin" uniqKey="Suwanarusk R" first="Rossarin" last="Suwanarusk">Rossarin Suwanarusk</name>
<affiliation wicri:level="1"><nlm:affiliation>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.</nlm:affiliation>
<country xml:lang="fr">Singapour</country>
<wicri:regionArea>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis</wicri:regionArea>
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<author><name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name>
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<country xml:lang="fr">Singapour</country>
<wicri:regionArea>Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis</wicri:regionArea>
<wicri:noRegion>Biopolis</wicri:noRegion>
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<author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</name>
<affiliation wicri:level="4"><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>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>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</wicri:regionArea>
<orgName type="university">Université d'Oxford</orgName>
<placeName><settlement type="city">Oxford</settlement>
<region type="nation">Angleterre</region>
<region type="région" nuts="1">Oxfordshire</region>
</placeName>
</affiliation>
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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>
<affiliation wicri:level="3"><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid</wicri:regionArea>
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<region nuts="2" type="region">Communauté de Madrid</region>
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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>
<affiliation wicri:level="3"><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid</wicri:regionArea>
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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>
<affiliation wicri:level="3"><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid</wicri:regionArea>
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<region nuts="2" type="region">Communauté de Madrid</region>
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<author><name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name>
<affiliation wicri:level="3"><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
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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 wicri:level="3"><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
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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 wicri:level="3"><nlm:affiliation>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.</nlm:affiliation>
<country xml:lang="fr">Espagne</country>
<wicri:regionArea>Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid</wicri:regionArea>
<placeName><settlement type="city">Madrid</settlement>
<region nuts="2" type="region">Communauté de Madrid</region>
</placeName>
</affiliation>
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<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation wicri:level="1"><nlm:affiliation>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.</nlm:affiliation>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel</wicri:regionArea>
<wicri:noRegion>Basel</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
<affiliation wicri:level="1"><nlm:affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland</wicri:regionArea>
<wicri:noRegion>Queensland</wicri:noRegion>
</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 wicri:level="1"><nlm:affiliation>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia.</nlm:affiliation>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland</wicri:regionArea>
<wicri:noRegion>Queensland</wicri:noRegion>
</affiliation>
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<author><name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<affiliation wicri:level="3"><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
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<author><name sortKey="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J" last="Delves">Michael J. Delves</name>
<affiliation wicri:level="3"><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sinden, Robert E" sort="Sinden, Robert E" uniqKey="Sinden R" first="Robert E" last="Sinden">Robert E. Sinden</name>
<affiliation wicri:level="3"><nlm:affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J" last="Fuchter">Matthew J. Fuchter</name>
<affiliation wicri:level="3"><nlm:affiliation>Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom.</nlm:affiliation>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Department of Chemistry, Imperial College London, South Kensington Campus, London</wicri:regionArea>
<placeName><settlement type="city">Londres</settlement>
<region type="country">Angleterre</region>
<region type="région" nuts="1">Grand Londres</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
<affiliation wicri:level="3"><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>
<country wicri:rule="url">France</country>
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<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
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<series><title level="j">Antimicrobial agents and chemotherapy</title>
<idno type="eISSN">1098-6596</idno>
<imprint><date when="2015" type="published">2015</date>
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<term>Antimalarials (chemistry)</term>
<term>Antimalarials (therapeutic use)</term>
<term>Azepines (chemistry)</term>
<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>
<term>Plasmodium falciparum (drug effects)</term>
<term>Plasmodium falciparum (pathogenicity)</term>
<term>Quinazolines (chemistry)</term>
<term>Quinazolines (therapeutic use)</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>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">25421480</PMID>
<DateCreated><Year>2015</Year>
<Month>01</Month>
<Day>28</Day>
</DateCreated>
<DateCompleted><Year>2015</Year>
<Month>10</Month>
<Day>08</Day>
</DateCompleted>
<DateRevised><Year>2015</Year>
<Month>10</Month>
<Day>28</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1098-6596</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>59</Volume>
<Issue>2</Issue>
<PubDate><Year>2015</Year>
<Month>Feb</Month>
</PubDate>
</JournalIssue>
<Title>Antimicrobial agents and chemotherapy</Title>
<ISOAbbreviation>Antimicrob. Agents Chemother.</ISOAbbreviation>
</Journal>
<ArticleTitle>Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.</ArticleTitle>
<Pagination><MedlinePgn>950-9</MedlinePgn>
</Pagination>
<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>
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<Initials>S</Initials>
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</AffiliationInfo>
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<Initials>VM</Initials>
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</AffiliationInfo>
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<Initials>A</Initials>
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<Initials>MJ</Initials>
<AffiliationInfo><Affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
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<Initials>RE</Initials>
<AffiliationInfo><Affiliation>Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom.</Affiliation>
</AffiliationInfo>
</Author>
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<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>
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<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>
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<MedlineTA>Antimicrob Agents Chemother</MedlineTA>
<NlmUniqueID>0315061</NlmUniqueID>
<ISSNLinking>0066-4804</ISSNLinking>
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<MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
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<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName>
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</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>
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<affiliations><list><country><li>Australie</li>
<li>Cambodge</li>
<li>Espagne</li>
<li>France</li>
<li>Royaume-Uni</li>
<li>Singapour</li>
<li>Suisse</li>
<li>Thaïlande</li>
</country>
<region><li>Angleterre</li>
<li>Communauté de Madrid</li>
<li>Grand Londres</li>
<li>Oxfordshire</li>
<li>Île-de-France</li>
</region>
<settlement><li>Londres</li>
<li>Madrid</li>
<li>Oxford</li>
<li>Paris</li>
</settlement>
<orgName><li>Université d'Oxford</li>
</orgName>
</list>
<tree><country name="France"><region name="Île-de-France"><name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A" last="Malmquist">Nicholas A. Malmquist</name>
</region>
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<name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
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<country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name>
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<name sortKey="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name>
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<name sortKey="Fuchter, Matthew J" sort="Fuchter, Matthew J" uniqKey="Fuchter M" first="Matthew J" last="Fuchter">Matthew J. Fuchter</name>
<name sortKey="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<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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<country name="Cambodge"><noRegion><name sortKey="Witkowski, Benoit" sort="Witkowski, Benoit" uniqKey="Witkowski B" first="Benoit" last="Witkowski">Benoit Witkowski</name>
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<country name="Singapour"><noRegion><name sortKey="Suwanarusk, Rossarin" sort="Suwanarusk, Rossarin" uniqKey="Suwanarusk R" first="Rossarin" last="Suwanarusk">Rossarin Suwanarusk</name>
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<name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name>
</country>
<country name="Thaïlande"><region name="Angleterre"><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</name>
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</country>
<country name="Espagne"><region name="Communauté de Madrid"><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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<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>
<name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name>
<name sortKey="Gamo, Francisco Javier" sort="Gamo, Francisco Javier" uniqKey="Gamo F" first="Francisco-Javier" last="Gamo">Francisco-Javier Gamo</name>
<name sortKey="Santos Martinez, Maria" sort="Santos Martinez, Maria" uniqKey="Santos Martinez M" first="María" last="Santos Martínez">María Santos Martínez</name>
<name sortKey="Sanz, Laura M" sort="Sanz, Laura M" uniqKey="Sanz L" first="Laura M" last="Sanz">Laura M. Sanz</name>
</country>
<country name="Suisse"><noRegion><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
</noRegion>
</country>
<country name="Australie"><noRegion><name sortKey="Duffy, Sandra" sort="Duffy, Sandra" uniqKey="Duffy S" first="Sandra" last="Duffy">Sandra Duffy</name>
</noRegion>
<name sortKey="Avery, Vicky M" sort="Avery, Vicky M" uniqKey="Avery V" first="Vicky M" last="Avery">Vicky M. Avery</name>
</country>
</tree>
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</record>

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   |texte=   Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.
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	Serveur d'exploration sur les relations entre la France et l'Australie
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.

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

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

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