Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.
Identifieur interne : 000619 ( Main/Exploration ); précédent : 000618; suivant : 000620Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.
Auteurs : Denise Rageot [Suisse] ; Thomas Bohnacker [Suisse] ; Anna Melone [Suisse] ; Jean-Baptiste Langlois [Suisse] ; Chiara Borsari [Suisse] ; Petra Hillmann [Suisse] ; Alexander M. Sele [Suisse] ; Florent Beaufils [Suisse] ; Marketa Zvelebil [Suisse] ; Paul Hebeisen [Suisse] ; Wolfgang Löscher [Allemagne] ; John Burke [Canada] ; Doriano Fabbro [Suisse] ; Matthias P. Wymann [Suisse]Source :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2018.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Barrière hémato-encéphalique (métabolisme), Complexe-1 cible mécanistique de la rapamycine (antagonistes et inhibiteurs), Complexe-2 cible mécanistique de la rapamycine (antagonistes et inhibiteurs), Composés azabicycliques (métabolisme), Composés azabicycliques (pharmacologie), Composés azabicycliques (usage thérapeutique), Conformation des protéines (MeSH), Crises épileptiques (traitement médicamenteux), Humains (MeSH), Lignée cellulaire tumorale (MeSH), Modèles moléculaires (MeSH), Phosphatidylinositol 3-kinases (composition chimique), Phosphatidylinositol 3-kinases (métabolisme), Prolifération cellulaire (effets des médicaments et des substances chimiques), Pyridines (métabolisme), Pyridines (pharmacologie), Pyridines (usage thérapeutique), Rats (MeSH), Souris (MeSH), Triazines (métabolisme), Triazines (pharmacologie), Triazines (usage thérapeutique).
- MESH :
- antagonistes et inhibiteurs : Complexe-1 cible mécanistique de la rapamycine, Complexe-2 cible mécanistique de la rapamycine.
- composition chimique : Phosphatidylinositol 3-kinases.
- effets des médicaments et des substances chimiques : Prolifération cellulaire.
- métabolisme : Barrière hémato-encéphalique, Composés azabicycliques, Phosphatidylinositol 3-kinases, Pyridines, Triazines.
- pharmacologie : Composés azabicycliques, Pyridines, Triazines.
- traitement médicamenteux : Crises épileptiques.
- usage thérapeutique : Composés azabicycliques, Pyridines, Triazines.
- Animaux, Conformation des protéines, Humains, Lignée cellulaire tumorale, Modèles moléculaires, Rats, Souris.
English descriptors
- KwdEn :
- Animals (MeSH), Azabicyclo Compounds (metabolism), Azabicyclo Compounds (pharmacology), Azabicyclo Compounds (therapeutic use), Blood-Brain Barrier (metabolism), Cell Line, Tumor (MeSH), Cell Proliferation (drug effects), Humans (MeSH), Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors), Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors), Mice (MeSH), Models, Molecular (MeSH), Phosphatidylinositol 3-Kinases (chemistry), Phosphatidylinositol 3-Kinases (metabolism), Protein Conformation (MeSH), Pyridines (metabolism), Pyridines (pharmacology), Pyridines (therapeutic use), Rats (MeSH), Seizures (drug therapy), Triazines (metabolism), Triazines (pharmacology), Triazines (therapeutic use).
- MESH :
- chemical , antagonists & inhibitors : Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2.
- chemical , chemistry : Phosphatidylinositol 3-Kinases.
- chemical , metabolism : Azabicyclo Compounds, Phosphatidylinositol 3-Kinases, Pyridines, Triazines.
- chemical , pharmacology : Azabicyclo Compounds, Pyridines, Triazines.
- chemical , therapeutic use : Azabicyclo Compounds, Pyridines, Triazines.
- drug effects : Cell Proliferation.
- drug therapy : Seizures.
- metabolism : Blood-Brain Barrier.
- Animals, Cell Line, Tumor, Humans, Mice, Models, Molecular, Protein Conformation, Rats.
Abstract
Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( Cmax) in plasma and brain was reached after 30 min, with a half-life ( t1/2) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.
DOI: 10.1021/acs.jmedchem.8b01262
PubMed: 30359003
Affiliations:
Links toward previous steps (curation, corpus...)
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Sele</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Beaufils, Florent" sort="Beaufils, Florent" uniqKey="Beaufils F" first="Florent" last="Beaufils">Florent Beaufils</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Zvelebil, Marketa" sort="Zvelebil, Marketa" uniqKey="Zvelebil M" first="Marketa" last="Zvelebil">Marketa Zvelebil</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Hebeisen, Paul" sort="Hebeisen, Paul" uniqKey="Hebeisen P" first="Paul" last="Hebeisen">Paul Hebeisen</name><affiliation wicri:level="1"><nlm:affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel </wicri:regionArea><wicri:noRegion>4057 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Loscher, Wolfgang" sort="Loscher, Wolfgang" uniqKey="Loscher W" first="Wolfgang" last="Löscher">Wolfgang Löscher</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Toxicology, and Pharmacy , University of Veterinary Medicine Hannover, and Center for Systems Neuroscience , 30559 Hannover , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pharmacology, Toxicology, and Pharmacy , University of Veterinary Medicine Hannover, and Center for Systems Neuroscience , 30559 Hannover </wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Burke, John" sort="Burke, John" uniqKey="Burke J" first="John" last="Burke">John Burke</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 </wicri:regionArea><wicri:noRegion>British Columbia V8W 2Y2 </wicri:noRegion></affiliation></author><author><name sortKey="Fabbro, Doriano" sort="Fabbro, Doriano" uniqKey="Fabbro D" first="Doriano" last="Fabbro">Doriano Fabbro</name><affiliation wicri:level="1"><nlm:affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel </wicri:regionArea><wicri:noRegion>4057 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Wymann, Matthias P" sort="Wymann, Matthias P" uniqKey="Wymann M" first="Matthias P" last="Wymann">Matthias P. Wymann</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:30359003</idno><idno type="pmid">30359003</idno><idno type="doi">10.1021/acs.jmedchem.8b01262</idno><idno type="wicri:Area/Main/Corpus">000420</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Corpus" wicri:corpus="PubMed">000420</idno><idno type="wicri:Area/Main/Curation">000420</idno><idno type="wicri:explorRef" wicri:stream="Main" wicri:step="Curation">000420</idno><idno type="wicri:Area/Main/Exploration">000420</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.</title><author><name sortKey="Rageot, Denise" sort="Rageot, Denise" uniqKey="Rageot D" first="Denise" last="Rageot">Denise Rageot</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Bohnacker, Thomas" sort="Bohnacker, Thomas" uniqKey="Bohnacker T" first="Thomas" last="Bohnacker">Thomas Bohnacker</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Melone, Anna" sort="Melone, Anna" uniqKey="Melone A" first="Anna" last="Melone">Anna Melone</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Langlois, Jean Baptiste" sort="Langlois, Jean Baptiste" uniqKey="Langlois J" first="Jean-Baptiste" last="Langlois">Jean-Baptiste Langlois</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Borsari, Chiara" sort="Borsari, Chiara" uniqKey="Borsari C" first="Chiara" last="Borsari">Chiara Borsari</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Hillmann, Petra" sort="Hillmann, Petra" uniqKey="Hillmann P" first="Petra" last="Hillmann">Petra Hillmann</name><affiliation wicri:level="1"><nlm:affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel </wicri:regionArea><wicri:noRegion>4057 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Sele, Alexander M" sort="Sele, Alexander M" uniqKey="Sele A" first="Alexander M" last="Sele">Alexander M. Sele</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Beaufils, Florent" sort="Beaufils, Florent" uniqKey="Beaufils F" first="Florent" last="Beaufils">Florent Beaufils</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Zvelebil, Marketa" sort="Zvelebil, Marketa" uniqKey="Zvelebil M" first="Marketa" last="Zvelebil">Marketa Zvelebil</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Hebeisen, Paul" sort="Hebeisen, Paul" uniqKey="Hebeisen P" first="Paul" last="Hebeisen">Paul Hebeisen</name><affiliation wicri:level="1"><nlm:affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel </wicri:regionArea><wicri:noRegion>4057 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Loscher, Wolfgang" sort="Loscher, Wolfgang" uniqKey="Loscher W" first="Wolfgang" last="Löscher">Wolfgang Löscher</name><affiliation wicri:level="3"><nlm:affiliation>Department of Pharmacology, Toxicology, and Pharmacy , University of Veterinary Medicine Hannover, and Center for Systems Neuroscience , 30559 Hannover , Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Pharmacology, Toxicology, and Pharmacy , University of Veterinary Medicine Hannover, and Center for Systems Neuroscience , 30559 Hannover </wicri:regionArea><placeName><region type="land" nuts="2">Basse-Saxe</region><settlement type="city">Hanovre</settlement></placeName></affiliation></author><author><name sortKey="Burke, John" sort="Burke, John" uniqKey="Burke J" first="John" last="Burke">John Burke</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 </wicri:regionArea><wicri:noRegion>British Columbia V8W 2Y2 </wicri:noRegion></affiliation></author><author><name sortKey="Fabbro, Doriano" sort="Fabbro, Doriano" uniqKey="Fabbro D" first="Doriano" last="Fabbro">Doriano Fabbro</name><affiliation wicri:level="1"><nlm:affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel </wicri:regionArea><wicri:noRegion>4057 Basel </wicri:noRegion></affiliation></author><author><name sortKey="Wymann, Matthias P" sort="Wymann, Matthias P" uniqKey="Wymann M" first="Matthias P" last="Wymann">Matthias P. Wymann</name><affiliation wicri:level="1"><nlm:affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</nlm:affiliation><country xml:lang="fr">Suisse</country><wicri:regionArea>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel </wicri:regionArea><wicri:noRegion>4058 Basel </wicri:noRegion></affiliation></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Azabicyclo Compounds (metabolism)</term><term>Azabicyclo Compounds (pharmacology)</term><term>Azabicyclo Compounds (therapeutic use)</term><term>Blood-Brain Barrier (metabolism)</term><term>Cell Line, Tumor (MeSH)</term><term>Cell Proliferation (drug effects)</term><term>Humans (MeSH)</term><term>Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)</term><term>Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors)</term><term>Mice (MeSH)</term><term>Models, Molecular (MeSH)</term><term>Phosphatidylinositol 3-Kinases (chemistry)</term><term>Phosphatidylinositol 3-Kinases (metabolism)</term><term>Protein Conformation (MeSH)</term><term>Pyridines (metabolism)</term><term>Pyridines (pharmacology)</term><term>Pyridines (therapeutic use)</term><term>Rats (MeSH)</term><term>Seizures (drug therapy)</term><term>Triazines (metabolism)</term><term>Triazines (pharmacology)</term><term>Triazines (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Barrière hémato-encéphalique (métabolisme)</term><term>Complexe-1 cible mécanistique de la rapamycine (antagonistes et inhibiteurs)</term><term>Complexe-2 cible mécanistique de la rapamycine (antagonistes et inhibiteurs)</term><term>Composés azabicycliques (métabolisme)</term><term>Composés azabicycliques (pharmacologie)</term><term>Composés azabicycliques (usage thérapeutique)</term><term>Conformation des protéines (MeSH)</term><term>Crises épileptiques (traitement médicamenteux)</term><term>Humains (MeSH)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Modèles moléculaires (MeSH)</term><term>Phosphatidylinositol 3-kinases (composition chimique)</term><term>Phosphatidylinositol 3-kinases (métabolisme)</term><term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term><term>Pyridines (métabolisme)</term><term>Pyridines (pharmacologie)</term><term>Pyridines (usage thérapeutique)</term><term>Rats (MeSH)</term><term>Souris (MeSH)</term><term>Triazines (métabolisme)</term><term>Triazines (pharmacologie)</term><term>Triazines (usage thérapeutique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Mechanistic Target of Rapamycin Complex 1</term><term>Mechanistic Target of Rapamycin Complex 2</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Phosphatidylinositol 3-Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Azabicyclo Compounds</term><term>Phosphatidylinositol 3-Kinases</term><term>Pyridines</term><term>Triazines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Azabicyclo Compounds</term><term>Pyridines</term><term>Triazines</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Azabicyclo Compounds</term><term>Pyridines</term><term>Triazines</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Complexe-2 cible mécanistique de la rapamycine</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Phosphatidylinositol 3-kinases</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Proliferation</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Seizures</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Prolifération cellulaire</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Blood-Brain Barrier</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Barrière hémato-encéphalique</term><term>Composés azabicycliques</term><term>Phosphatidylinositol 3-kinases</term><term>Pyridines</term><term>Triazines</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Composés azabicycliques</term><term>Pyridines</term><term>Triazines</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Crises épileptiques</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Composés azabicycliques</term><term>Pyridines</term><term>Triazines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line, Tumor</term><term>Humans</term><term>Mice</term><term>Models, Molecular</term><term>Protein Conformation</term><term>Rats</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Conformation des protéines</term><term>Humains</term><term>Lignée cellulaire tumorale</term><term>Modèles moléculaires</term><term>Rats</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( C<sub>max</sub>) in plasma and brain was reached after 30 min, with a half-life ( t<sub>1/2</sub>) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">30359003</PMID><DateCompleted><Year>2019</Year><Month>09</Month><Day>30</Day></DateCompleted><DateRevised><Year>2019</Year><Month>09</Month><Day>30</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1520-4804</ISSN><JournalIssue CitedMedium="Internet"><Volume>61</Volume><Issue>22</Issue><PubDate><Year>2018</Year><Month>11</Month><Day>21</Day></PubDate></JournalIssue><Title>Journal of medicinal chemistry</Title><ISOAbbreviation>J Med Chem</ISOAbbreviation></Journal><ArticleTitle>Discovery and Preclinical Characterization of 5-[4,6-Bis({3-oxa-8-azabicyclo[3.2.1]octan-8-yl})-1,3,5-triazin-2-yl]-4-(difluoromethyl)pyridin-2-amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders.</ArticleTitle><Pagination><MedlinePgn>10084-10105</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/acs.jmedchem.8b01262</ELocationID><Abstract><AbstractText>Mechanistic target of rapamycin (mTOR) promotes cell proliferation, growth, and survival and is overactivated in many tumors and central nervous system disorders. PQR620 (3) is a novel, potent, selective, and brain penetrable inhibitor of mTORC1/2 kinase. PQR620 (3) showed excellent selectivity for mTOR over PI3K and protein kinases and efficiently prevented cancer cell growth in a 66 cancer cell line panel. In C57BL/6J and Sprague-Dawley mice, maximum concentration ( C<sub>max</sub>) in plasma and brain was reached after 30 min, with a half-life ( t<sub>1/2</sub>) > 5 h. In an ovarian carcinoma mouse xenograft model (OVCAR-3), daily dosing of PQR620 (3) inhibited tumor growth significantly. Moreover, PQR620 (3) attenuated epileptic seizures in a tuberous sclerosis complex (TSC) mouse model. In conclusion, PQR620 (3) inhibits mTOR kinase potently and selectively, shows antitumor effects in vitro and in vivo, and promises advantages in CNS indications due to its brain/plasma distribution ratio.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Rageot</LastName><ForeName>Denise</ForeName><Initials>D</Initials><Identifier Source="ORCID">0000-0002-2833-5481</Identifier><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bohnacker</LastName><ForeName>Thomas</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Melone</LastName><ForeName>Anna</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Langlois</LastName><ForeName>Jean-Baptiste</ForeName><Initials>JB</Initials><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Borsari</LastName><ForeName>Chiara</ForeName><Initials>C</Initials><Identifier Source="ORCID">0000-0002-4688-8362</Identifier><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hillmann</LastName><ForeName>Petra</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sele</LastName><ForeName>Alexander M</ForeName><Initials>AM</Initials><Identifier Source="ORCID">0000-0002-4903-7934</Identifier><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Beaufils</LastName><ForeName>Florent</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zvelebil</LastName><ForeName>Marketa</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hebeisen</LastName><ForeName>Paul</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Löscher</LastName><ForeName>Wolfgang</ForeName><Initials>W</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, Toxicology, and Pharmacy , University of Veterinary Medicine Hannover, and Center for Systems Neuroscience , 30559 Hannover , Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Burke</LastName><ForeName>John</ForeName><Initials>J</Initials><Identifier Source="ORCID">0000-0001-7904-9859</Identifier><AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fabbro</LastName><ForeName>Doriano</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wymann</LastName><ForeName>Matthias P</ForeName><Initials>MP</Initials><Identifier Source="ORCID">0000-0003-3349-4281</Identifier><AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</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>2018</Year><Month>11</Month><Day>14</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Med Chem</MedlineTA><NlmUniqueID>9716531</NlmUniqueID><ISSNLinking>0022-2623</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D053961">Azabicyclo Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011725">Pyridines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014227">Triazines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C000629977">pqr620</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.1.-</RegistryNumber><NameOfSubstance UI="D019869">Phosphatidylinositol 3-Kinases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076222">Mechanistic Target of Rapamycin Complex 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber><NameOfSubstance UI="D000076225">Mechanistic Target of Rapamycin Complex 2</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D053961" MajorTopicYN="N">Azabicyclo Compounds</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001812" MajorTopicYN="N">Blood-Brain Barrier</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D049109" MajorTopicYN="N">Cell Proliferation</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000076222" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 1</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000076225" MajorTopicYN="N">Mechanistic Target of Rapamycin Complex 2</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011725" MajorTopicYN="N">Pyridines</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012640" MajorTopicYN="N">Seizures</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014227" MajorTopicYN="N">Triazines</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2018</Year><Month>10</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2019</Year><Month>10</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2018</Year><Month>10</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30359003</ArticleId><ArticleId IdType="doi">10.1021/acs.jmedchem.8b01262</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Allemagne</li><li>Canada</li><li>Suisse</li></country><region><li>Basse-Saxe</li></region><settlement><li>Hanovre</li></settlement></list><tree><country name="Suisse"><noRegion><name sortKey="Rageot, Denise" sort="Rageot, Denise" uniqKey="Rageot D" first="Denise" last="Rageot">Denise Rageot</name></noRegion><name sortKey="Beaufils, Florent" sort="Beaufils, Florent" uniqKey="Beaufils F" first="Florent" last="Beaufils">Florent Beaufils</name><name sortKey="Bohnacker, Thomas" sort="Bohnacker, Thomas" uniqKey="Bohnacker T" first="Thomas" last="Bohnacker">Thomas Bohnacker</name><name sortKey="Borsari, Chiara" sort="Borsari, Chiara" uniqKey="Borsari C" first="Chiara" last="Borsari">Chiara Borsari</name><name sortKey="Fabbro, Doriano" sort="Fabbro, Doriano" uniqKey="Fabbro D" first="Doriano" last="Fabbro">Doriano Fabbro</name><name sortKey="Hebeisen, Paul" sort="Hebeisen, Paul" uniqKey="Hebeisen P" first="Paul" last="Hebeisen">Paul Hebeisen</name><name sortKey="Hillmann, Petra" sort="Hillmann, Petra" uniqKey="Hillmann P" first="Petra" last="Hillmann">Petra Hillmann</name><name sortKey="Langlois, Jean Baptiste" sort="Langlois, Jean Baptiste" uniqKey="Langlois J" first="Jean-Baptiste" last="Langlois">Jean-Baptiste Langlois</name><name sortKey="Melone, Anna" sort="Melone, Anna" uniqKey="Melone A" first="Anna" last="Melone">Anna Melone</name><name sortKey="Sele, Alexander M" sort="Sele, Alexander M" uniqKey="Sele A" first="Alexander M" last="Sele">Alexander M. Sele</name><name sortKey="Wymann, Matthias P" sort="Wymann, Matthias P" uniqKey="Wymann M" first="Matthias P" last="Wymann">Matthias P. Wymann</name><name sortKey="Zvelebil, Marketa" sort="Zvelebil, Marketa" uniqKey="Zvelebil M" first="Marketa" last="Zvelebil">Marketa Zvelebil</name></country><country name="Allemagne"><region name="Basse-Saxe"><name sortKey="Loscher, Wolfgang" sort="Loscher, Wolfgang" uniqKey="Loscher W" first="Wolfgang" last="Löscher">Wolfgang Löscher</name></region></country><country name="Canada"><noRegion><name sortKey="Burke, John" sort="Burke, John" uniqKey="Burke J" first="John" last="Burke">John Burke</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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