AustralieFrV1, Main, Exploration, bibRecord, 002D02

Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans

Identifieur interne : 002D02 ( Main/Exploration ); précédent : 002D01; suivant : 002D03

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 [Royaume-Uni, 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 [ 0066-4804 ] ; 2015.

RBID : PMC:4335868

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.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335868

DOI: 10.1128/AAC.04419-14
PubMed: 25421480
PubMed Central: 4335868

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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<affiliation wicri:level="3"><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>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>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sundriyal, Sandeep" sort="Sundriyal, Sandeep" uniqKey="Sundriyal S" first="Sandeep" last="Sundriyal">Sandeep Sundriyal</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff>
<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="Caron, Joachim" sort="Caron, Joachim" uniqKey="Caron J" first="Joachim" last="Caron">Joachim Caron</name>
<affiliation wicri:level="3"><nlm:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff>
<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="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name>
<affiliation wicri:level="3"><nlm:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>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>
</placeName>
</affiliation>
</author>
<author><name sortKey="Witkowski, Benoit" sort="Witkowski, Benoit" uniqKey="Witkowski B" first="Benoit" last="Witkowski">Benoit Witkowski</name>
<affiliation wicri:level="1"><nlm:aff id="aff4">Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</nlm:aff>
<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>
</affiliation>
</author>
<author><name sortKey="Menard, Didier" sort="Menard, Didier" uniqKey="Menard D" first="Didier" last="Menard">Didier Menard</name>
<affiliation wicri:level="1"><nlm:aff id="aff4">Institut Pasteur du Cambodge, Malaria Molecular Epidemiology Unit, Phnom Penh, Cambodia</nlm:aff>
<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>
</affiliation>
</author>
<author><name sortKey="Suwanarusk, Rossarin" sort="Suwanarusk, Rossarin" uniqKey="Suwanarusk R" first="Rossarin" last="Suwanarusk">Rossarin Suwanarusk</name>
<affiliation wicri:level="1"><nlm:aff id="aff5">Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</nlm:aff>
<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>
</affiliation>
</author>
<author><name sortKey="Renia, Laurent" sort="Renia, Laurent" uniqKey="Renia L" first="Laurent" last="Renia">Laurent Renia</name>
<affiliation wicri:level="1"><nlm:aff id="aff5">Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore</nlm:aff>
<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>
</affiliation>
</author>
<author><name sortKey="Nosten, Francois" sort="Nosten, Francois" uniqKey="Nosten F" first="Francois" last="Nosten">Francois Nosten</name>
<affiliation wicri:level="4"><nlm:aff id="aff6">Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford</wicri:regionArea>
<placeName><settlement type="city">Oxford</settlement>
<region type="country">Angleterre</region>
<region type="comté" nuts="2">Oxfordshire</region>
<settlement type="city">Oxford</settlement>
</placeName>
<orgName type="university">Université d'Oxford</orgName>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff7">Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, Thailand</nlm:aff>
<country xml:lang="fr">Thaïlande</country>
<wicri:regionArea>Shoklo Malaria Research Unit, Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot</wicri:regionArea>
<wicri:noRegion>Mae Sot</wicri:noRegion>
</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 wicri:level="3"><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff>
<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>
</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 wicri:level="3"><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff>
<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>
</author>
<author><name sortKey="Martinez, Maria Santos" sort="Martinez, Maria Santos" uniqKey="Martinez M" first="María Santos" last="Martínez">María Santos Martínez</name>
<affiliation wicri:level="3"><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff>
<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>
</author>
<author><name sortKey="Ferrer, Santiago" sort="Ferrer, Santiago" uniqKey="Ferrer S" first="Santiago" last="Ferrer">Santiago Ferrer</name>
<affiliation wicri:level="3"><nlm:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff>
<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>
</author>
<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:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff>
<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>
</author>
<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:aff id="aff8">Tres Cantos Medicines Development Campus, Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain</nlm:aff>
<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>
</author>
<author><name sortKey="Wittlin, Sergio" sort="Wittlin, Sergio" uniqKey="Wittlin S" first="Sergio" last="Wittlin">Sergio Wittlin</name>
<affiliation wicri:level="1"><nlm:aff id="aff9">Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel, Switzerland</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>Parasite Chemotherapy Unit, Swiss Tropical and Public Health Institute, Basel</wicri:regionArea>
<wicri:noRegion>Basel</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="aff10">University of Basel, Basel, Switzerland</nlm:aff>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>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:aff id="aff11">Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</nlm:aff>
<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:aff id="aff11">Discovery Biology, Eskitis Institute, Griffith University, Nathan Campus, Brisbane, Queensland, Australia</nlm:aff>
<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="Ruecker, Andrea" sort="Ruecker, Andrea" uniqKey="Ruecker A" first="Andrea" last="Ruecker">Andrea Ruecker</name>
<affiliation wicri:level="3"><nlm:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff>
<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="Delves, Michael J" sort="Delves, Michael J" uniqKey="Delves M" first="Michael J." last="Delves">Michael J. Delves</name>
<affiliation wicri:level="3"><nlm:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff>
<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:aff id="aff12">Division of Cell and Molecular Biology, Imperial College London, South Kensington, London, United Kingdom</nlm:aff>
<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:aff id="aff3">Department of Chemistry, Imperial College London, South Kensington Campus, London, United Kingdom</nlm:aff>
<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:aff id="aff1">Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Unité de Biologie des Interactions Hôte-Parasite, Institut Pasteur, Paris</wicri:regionArea>
<placeName><region type="region">Île-de-France</region>
<region type="old region">Île-de-France</region>
<settlement type="city">Paris</settlement>
</placeName>
</affiliation>
<affiliation wicri:level="3"><nlm:aff id="aff2">Centre National de la Recherche Scientifique, Unité de Recherche Associée 2581, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>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>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Antimicrobial Agents and Chemotherapy</title>
<idno type="ISSN">0066-4804</idno>
<idno type="eISSN">1098-6596</idno>
<imprint><date when="2015">2015</date>
</imprint>
</series>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<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>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Antipaludiques ()</term>
<term>Antipaludiques (usage thérapeutique)</term>
<term>Azépines ()</term>
<term>Azépines (usage thérapeutique)</term>
<term>Cellules HepG2</term>
<term>Femelle</term>
<term>Histone-lysine N-methyltransferase (antagonistes et inhibiteurs)</term>
<term>Humains</term>
<term>Paludisme (traitement médicamenteux)</term>
<term>Paludisme à Plasmodium falciparum (traitement médicamenteux)</term>
<term>Plasmodium berghei ()</term>
<term>Plasmodium berghei (pathogénicité)</term>
<term>Plasmodium falciparum ()</term>
<term>Plasmodium falciparum (pathogénicité)</term>
<term>Quinazolines ()</term>
<term>Quinazolines (usage thérapeutique)</term>
<term>Souris</term>
<term>Souris SCID</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Histone-Lysine N-Methyltransferase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antimalarials</term>
<term>Azepines</term>
<term>Quinazolines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antimalarials</term>
<term>Azepines</term>
<term>Quinazolines</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Histone-lysine N-methyltransferase</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Plasmodium berghei</term>
<term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Malaria</term>
<term>Malaria, Falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Plasmodium berghei</term>
<term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Plasmodium berghei</term>
<term>Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Paludisme</term>
<term>Paludisme à Plasmodium falciparum</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antipaludiques</term>
<term>Azépines</term>
<term>Quinazolines</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Female</term>
<term>Hep G2 Cells</term>
<term>Humans</term>
<term>Mice</term>
<term>Mice, SCID</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Antipaludiques</term>
<term>Azépines</term>
<term>Cellules HepG2</term>
<term>Femelle</term>
<term>Humains</term>
<term>Plasmodium berghei</term>
<term>Plasmodium falciparum</term>
<term>Quinazolines</term>
<term>Souris</term>
<term>Souris SCID</term>
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<front><div type="abstract" xml:lang="en"><p>Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising <italic>in vitro</italic>
 parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for <italic>in vitro</italic>
 and <italic>in vivo</italic>
 efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent <italic>in vitro</italic>
 activity, with 50% inhibitory concentrations (IC<sub>50</sub>
s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory <named-content content-type="genus-species">Plasmodium falciparum</named-content>
 isolates. Activities against <italic>ex vivo</italic>
 clinical isolates of both <named-content content-type="genus-species">P. falciparum</named-content>
 and <named-content content-type="genus-species">Plasmodium vivax</named-content>
 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 <italic>in vivo</italic>
 mouse models of <named-content content-type="genus-species">Plasmodium berghei</named-content>
 and <named-content content-type="genus-species">P. falciparum</named-content>
 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.</p>
</div>
</front>
</TEI>
<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>
<name sortKey="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name>
<name sortKey="Chen, Patty" sort="Chen, Patty" uniqKey="Chen P" first="Patty" last="Chen">Patty Chen</name>
<name sortKey="Malmquist, Nicholas A" sort="Malmquist, Nicholas A" uniqKey="Malmquist N" first="Nicholas A." last="Malmquist">Nicholas A. Malmquist</name>
<name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
<name sortKey="Scherf, Artur" sort="Scherf, Artur" uniqKey="Scherf A" first="Artur" last="Scherf">Artur Scherf</name>
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   |area=    AustralieFrV1
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   |type=    RBID
   |clé=     PMC:4335868
   |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

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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	Serveur d'exploration sur les relations entre la France et l'Australie
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