RapamycinFungusV1, Main, Exploration, bibRecord, 000411

(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

Identifieur interne : 000411 ( Main/Exploration ); précédent : 000410; suivant : 000412

(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

Auteurs : Denise Rageot [Suisse] ; Thomas Bohnacker [Suisse] ; Erhan Keles [Suisse] ; Jacob A. Mcphail [Canada] ; Reece M. Hoffmann [Canada] ; Anna Melone [Suisse] ; Chiara Borsari [Suisse] ; Rohitha Sriramaratnam [Suisse] ; Alexander M. Sele [Suisse] ; Florent Beaufils [Suisse] ; Paul Hebeisen [Suisse] ; Doriano Fabbro [Suisse] ; Petra Hillmann [Suisse] ; John E. Burke [Canada] ; Matthias P. Wymann [Suisse]

Source :

Journal of medicinal chemistry [ 1520-4804 ] ; 2019.

RBID : pubmed:31244112

Descripteurs français

English descriptors

KwdEn :
- Aminopyridines (chemical synthesis), Aminopyridines (metabolism), Aminopyridines (pharmacology), Animals (MeSH), Antineoplastic Agents (chemical synthesis), Antineoplastic Agents (metabolism), Antineoplastic Agents (pharmacology), Brain (metabolism), Cell Line, Tumor (MeSH), Dogs (MeSH), Female (MeSH), Humans (MeSH), Male (MeSH), Mice, Inbred BALB C (MeSH), Mice, Inbred C57BL (MeSH), Microsomes, Liver (metabolism), Molecular Docking Simulation (MeSH), Molecular Structure (MeSH), Morpholines (chemical synthesis), Morpholines (metabolism), Morpholines (pharmacology), Phosphatidylinositol 3-Kinases (metabolism), Phosphoinositide-3 Kinase Inhibitors (chemical synthesis), Phosphoinositide-3 Kinase Inhibitors (metabolism), Phosphoinositide-3 Kinase Inhibitors (pharmacology), Protein Binding (MeSH), Pyridines (chemical synthesis), Pyridines (metabolism), Pyridines (pharmacology), Rats, Wistar (MeSH), Structure-Activity Relationship (MeSH), TOR Serine-Threonine Kinases (antagonists & inhibitors), TOR Serine-Threonine Kinases (metabolism), Triazines (chemical synthesis), Triazines (metabolism), Triazines (pharmacology), Xenograft Model Antitumor Assays (MeSH).
MESH :
- chemical , antagonists & inhibitors : TOR Serine-Threonine Kinases.
- chemical , chemical synthesis : Aminopyridines, Antineoplastic Agents, Morpholines, Phosphoinositide-3 Kinase Inhibitors, Pyridines, Triazines.
- chemical , metabolism : Aminopyridines, Antineoplastic Agents, Morpholines, Phosphoinositide-3 Kinase Inhibitors, Pyridines, TOR Serine-Threonine Kinases, Triazines.
- chemical , pharmacology : Aminopyridines, Antineoplastic Agents, Morpholines, Phosphoinositide-3 Kinase Inhibitors, Pyridines, Triazines.
- metabolism : Brain, Microsomes, Liver, Phosphatidylinositol 3-Kinases.
- Animals, Cell Line, Tumor, Dogs, Female, Humans, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Docking Simulation, Molecular Structure, Protein Binding, Rats, Wistar, Structure-Activity Relationship, Xenograft Model Antitumor Assays.

Abstract

The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: (S)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound 6), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound 6 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound 6 prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound 6 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify 6 for further development as a therapeutic agent in oncology.

DOI: 10.1021/acs.jmedchem.9b00525
PubMed: 31244112

Affiliations:

Canada, Suisse

Links toward previous steps (curation, corpus...)

to stream Main, to step Corpus: 000241
to stream Main, to step Curation: 000241

Le document en format XML

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)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.</title>
<author><name sortKey="Rageot, Denise" sort="Rageot, Denise" uniqKey="Rageot D" first="Denise" last="Rageot">Denise Rageot</name>
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<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>
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<author><name sortKey="Bohnacker, Thomas" sort="Bohnacker, Thomas" uniqKey="Bohnacker T" first="Thomas" last="Bohnacker">Thomas Bohnacker</name>
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<author><name sortKey="Mcphail, Jacob A" sort="Mcphail, Jacob A" uniqKey="Mcphail J" first="Jacob A" last="Mcphail">Jacob A. Mcphail</name>
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<author><name sortKey="Sriramaratnam, Rohitha" sort="Sriramaratnam, Rohitha" uniqKey="Sriramaratnam R" first="Rohitha" last="Sriramaratnam">Rohitha Sriramaratnam</name>
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<author><name sortKey="Sele, Alexander M" sort="Sele, Alexander M" uniqKey="Sele A" first="Alexander M" last="Sele">Alexander M. Sele</name>
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<author><name sortKey="Beaufils, Florent" sort="Beaufils, Florent" uniqKey="Beaufils F" first="Florent" last="Beaufils">Florent Beaufils</name>
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<author><name sortKey="Hebeisen, Paul" sort="Hebeisen, Paul" uniqKey="Hebeisen P" first="Paul" last="Hebeisen">Paul Hebeisen</name>
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<author><name sortKey="Fabbro, Doriano" sort="Fabbro, Doriano" uniqKey="Fabbro D" first="Doriano" last="Fabbro">Doriano Fabbro</name>
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<author><name sortKey="Hillmann, Petra" sort="Hillmann, Petra" uniqKey="Hillmann P" first="Petra" last="Hillmann">Petra Hillmann</name>
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<author><name sortKey="Burke, John E" sort="Burke, John E" uniqKey="Burke J" first="John E" last="Burke">John E. Burke</name>
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<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>
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<author><name sortKey="Wymann, Matthias P" sort="Wymann, Matthias P" uniqKey="Wymann M" first="Matthias P" last="Wymann">Matthias P. Wymann</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">(<i>S</i>
)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.</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>
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<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>
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<author><name sortKey="Keles, Erhan" sort="Keles, Erhan" uniqKey="Keles E" first="Erhan" last="Keles">Erhan Keles</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>
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<author><name sortKey="Mcphail, Jacob A" sort="Mcphail, Jacob A" uniqKey="Mcphail J" first="Jacob A" last="Mcphail">Jacob A. Mcphail</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="Hoffmann, Reece M" sort="Hoffmann, Reece M" uniqKey="Hoffmann R" first="Reece M" last="Hoffmann">Reece M. Hoffmann</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="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="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="Sriramaratnam, Rohitha" sort="Sriramaratnam, Rohitha" uniqKey="Sriramaratnam R" first="Rohitha" last="Sriramaratnam">Rohitha Sriramaratnam</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="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="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 60C , 4057 Basel , Switzerland.</nlm:affiliation>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel </wicri:regionArea>
<wicri:noRegion>4057 Basel </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 60C , 4057 Basel , Switzerland.</nlm:affiliation>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel </wicri:regionArea>
<wicri:noRegion>4057 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 60C , 4057 Basel , Switzerland.</nlm:affiliation>
<country xml:lang="fr">Suisse</country>
<wicri:regionArea>PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel </wicri:regionArea>
<wicri:noRegion>4057 Basel </wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Burke, John E" sort="Burke, John E" uniqKey="Burke J" first="John E" last="Burke">John E. 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="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>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aminopyridines (chemical synthesis)</term>
<term>Aminopyridines (metabolism)</term>
<term>Aminopyridines (pharmacology)</term>
<term>Animals (MeSH)</term>
<term>Antineoplastic Agents (chemical synthesis)</term>
<term>Antineoplastic Agents (metabolism)</term>
<term>Antineoplastic Agents (pharmacology)</term>
<term>Brain (metabolism)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Dogs (MeSH)</term>
<term>Female (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Male (MeSH)</term>
<term>Mice, Inbred BALB C (MeSH)</term>
<term>Mice, Inbred C57BL (MeSH)</term>
<term>Microsomes, Liver (metabolism)</term>
<term>Molecular Docking Simulation (MeSH)</term>
<term>Molecular Structure (MeSH)</term>
<term>Morpholines (chemical synthesis)</term>
<term>Morpholines (metabolism)</term>
<term>Morpholines (pharmacology)</term>
<term>Phosphatidylinositol 3-Kinases (metabolism)</term>
<term>Phosphoinositide-3 Kinase Inhibitors (chemical synthesis)</term>
<term>Phosphoinositide-3 Kinase Inhibitors (metabolism)</term>
<term>Phosphoinositide-3 Kinase Inhibitors (pharmacology)</term>
<term>Protein Binding (MeSH)</term>
<term>Pyridines (chemical synthesis)</term>
<term>Pyridines (metabolism)</term>
<term>Pyridines (pharmacology)</term>
<term>Rats, Wistar (MeSH)</term>
<term>Structure-Activity Relationship (MeSH)</term>
<term>TOR Serine-Threonine Kinases (antagonists & inhibitors)</term>
<term>TOR Serine-Threonine Kinases (metabolism)</term>
<term>Triazines (chemical synthesis)</term>
<term>Triazines (metabolism)</term>
<term>Triazines (pharmacology)</term>
<term>Xenograft Model Antitumor Assays (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Aminopyridines (métabolisme)</term>
<term>Aminopyridines (pharmacologie)</term>
<term>Aminopyridines (synthèse chimique)</term>
<term>Animaux (MeSH)</term>
<term>Antinéoplasiques (métabolisme)</term>
<term>Antinéoplasiques (pharmacologie)</term>
<term>Antinéoplasiques (synthèse chimique)</term>
<term>Chiens (MeSH)</term>
<term>Encéphale (métabolisme)</term>
<term>Femelle (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Liaison aux protéines (MeSH)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Microsomes du foie (métabolisme)</term>
<term>Morpholines (métabolisme)</term>
<term>Morpholines (pharmacologie)</term>
<term>Morpholines (synthèse chimique)</term>
<term>Mâle (MeSH)</term>
<term>Phosphatidylinositol 3-kinases (métabolisme)</term>
<term>Pyridines (métabolisme)</term>
<term>Pyridines (pharmacologie)</term>
<term>Pyridines (synthèse chimique)</term>
<term>Rat Wistar (MeSH)</term>
<term>Relation structure-activité (MeSH)</term>
<term>Simulation de docking moléculaire (MeSH)</term>
<term>Souris de lignée BALB C (MeSH)</term>
<term>Souris de lignée C57BL (MeSH)</term>
<term>Structure moléculaire (MeSH)</term>
<term>Sérine-thréonine kinases TOR (antagonistes et inhibiteurs)</term>
<term>Sérine-thréonine kinases TOR (métabolisme)</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe (MeSH)</term>
<term>Triazines (métabolisme)</term>
<term>Triazines (pharmacologie)</term>
<term>Triazines (synthèse chimique)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>TOR Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Aminopyridines</term>
<term>Antineoplastic Agents</term>
<term>Morpholines</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
<term>Pyridines</term>
<term>Triazines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Aminopyridines</term>
<term>Antineoplastic Agents</term>
<term>Morpholines</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
<term>Pyridines</term>
<term>TOR Serine-Threonine Kinases</term>
<term>Triazines</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Aminopyridines</term>
<term>Antineoplastic Agents</term>
<term>Morpholines</term>
<term>Phosphoinositide-3 Kinase Inhibitors</term>
<term>Pyridines</term>
<term>Triazines</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Sérine-thréonine kinases TOR</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Brain</term>
<term>Microsomes, Liver</term>
<term>Phosphatidylinositol 3-Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Aminopyridines</term>
<term>Antinéoplasiques</term>
<term>Encéphale</term>
<term>Microsomes du foie</term>
<term>Morpholines</term>
<term>Phosphatidylinositol 3-kinases</term>
<term>Pyridines</term>
<term>Sérine-thréonine kinases TOR</term>
<term>Triazines</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Aminopyridines</term>
<term>Antinéoplasiques</term>
<term>Morpholines</term>
<term>Pyridines</term>
<term>Triazines</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Aminopyridines</term>
<term>Antinéoplasiques</term>
<term>Morpholines</term>
<term>Pyridines</term>
<term>Triazines</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Dogs</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Mice, Inbred BALB C</term>
<term>Mice, Inbred C57BL</term>
<term>Molecular Docking Simulation</term>
<term>Molecular Structure</term>
<term>Protein Binding</term>
<term>Rats, Wistar</term>
<term>Structure-Activity Relationship</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Chiens</term>
<term>Femelle</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire tumorale</term>
<term>Mâle</term>
<term>Rat Wistar</term>
<term>Relation structure-activité</term>
<term>Simulation de docking moléculaire</term>
<term>Souris de lignée BALB C</term>
<term>Souris de lignée C57BL</term>
<term>Structure moléculaire</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: (<i>S</i>
)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound <b>6</b>
), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound <b>6</b>
 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound <b>6</b>
 prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound <b>6</b>
 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify <b>6</b>
 for further development as a therapeutic agent in oncology.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">31244112</PMID>
<DateCompleted><Year>2020</Year>
<Month>06</Month>
<Day>22</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>08</Month>
<Day>03</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1520-4804</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>62</Volume>
<Issue>13</Issue>
<PubDate><Year>2019</Year>
<Month>07</Month>
<Day>11</Day>
</PubDate>
</JournalIssue>
<Title>Journal of medicinal chemistry</Title>
<ISOAbbreviation>J Med Chem</ISOAbbreviation>
</Journal>
<ArticleTitle>(<i>S</i>
)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.</ArticleTitle>
<Pagination><MedlinePgn>6241-6261</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1021/acs.jmedchem.9b00525</ELocationID>
<Abstract><AbstractText>The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is frequently overactivated in cancer, and drives cell growth, proliferation, survival, and metastasis. Here, we report a structure-activity relationship study, which led to the discovery of a drug-like adenosine 5'-triphosphate-site PI3K/mTOR kinase inhibitor: (<i>S</i>
)-4-(difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530, compound <b>6</b>
), which qualifies as a clinical candidate due to its potency and specificity for PI3K and mTOR kinases, and its pharmacokinetic properties, including brain penetration. Compound <b>6</b>
 showed excellent selectivity over a wide panel of kinases and an excellent selectivity against unrelated receptor enzymes and ion channels. Moreover, compound <b>6</b>
 prevented cell growth in a cancer cell line panel. The preclinical in vivo characterization of compound <b>6</b>
 in an OVCAR-3 xenograft model demonstrated good oral bioavailability, excellent brain penetration, and efficacy. Initial toxicity studies in rats and dogs qualify <b>6</b>
 for further development as a therapeutic agent in oncology.</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>Keles</LastName>
<ForeName>Erhan</ForeName>
<Initials>E</Initials>
<AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>McPhail</LastName>
<ForeName>Jacob A</ForeName>
<Initials>JA</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hoffmann</LastName>
<ForeName>Reece M</ForeName>
<Initials>RM</Initials>
<AffiliationInfo><Affiliation>Department of Biochemistry and Microbiology , University of Victoria , Victoria , British Columbia V8W 2Y2 , Canada.</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>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>Sriramaratnam</LastName>
<ForeName>Rohitha</ForeName>
<Initials>R</Initials>
<AffiliationInfo><Affiliation>Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 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>Hebeisen</LastName>
<ForeName>Paul</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Fabbro</LastName>
<ForeName>Doriano</ForeName>
<Initials>D</Initials>
<AffiliationInfo><Affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Hillmann</LastName>
<ForeName>Petra</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>PIQUR Therapeutics AG , Hochbergerstrasse 60C , 4057 Basel , Switzerland.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Burke</LastName>
<ForeName>John E</ForeName>
<Initials>JE</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>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>2019</Year>
<Month>06</Month>
<Day>20</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="D000631">Aminopyridines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000970">Antineoplastic Agents</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D009025">Morpholines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="C000707853">PQR530</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D000081082">Phosphoinositide-3 Kinase Inhibitors</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D011725">Pyridines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>0</RegistryNumber>
<NameOfSubstance UI="D014227">Triazines</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber>
<NameOfSubstance UI="C546842">MTOR protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.1.1</RegistryNumber>
<NameOfSubstance UI="D058570">TOR Serine-Threonine Kinases</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>IM</CitationSubset>
<MeshHeadingList><MeshHeading><DescriptorName UI="D000631" MajorTopicYN="N">Aminopyridines</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000970" MajorTopicYN="N">Antineoplastic Agents</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D001921" MajorTopicYN="N">Brain</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D004285" MajorTopicYN="N">Dogs</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008807" MajorTopicYN="N">Mice, Inbred BALB C</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008810" MajorTopicYN="N">Mice, Inbred C57BL</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D008862" MajorTopicYN="N">Microsomes, Liver</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D062105" MajorTopicYN="N">Molecular Docking Simulation</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D009025" MajorTopicYN="N">Morpholines</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D019869" MajorTopicYN="N">Phosphatidylinositol 3-Kinases</DescriptorName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D000081082" MajorTopicYN="N">Phosphoinositide-3 Kinase Inhibitors</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011485" MajorTopicYN="N">Protein Binding</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D011725" MajorTopicYN="N">Pyridines</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D017208" MajorTopicYN="N">Rats, Wistar</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D013329" MajorTopicYN="N">Structure-Activity Relationship</DescriptorName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D058570" MajorTopicYN="N">TOR Serine-Threonine Kinases</DescriptorName>
<QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D014227" MajorTopicYN="N">Triazines</DescriptorName>
<QualifierName UI="Q000138" MajorTopicYN="N">chemical synthesis</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
<QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName>
</MeshHeading>
<MeshHeading><DescriptorName UI="D023041" MajorTopicYN="N">Xenograft Model Antitumor Assays</DescriptorName>
</MeshHeading>
</MeshHeadingList>
</MedlineCitation>
<PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2019</Year>
<Month>6</Month>
<Day>28</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline"><Year>2020</Year>
<Month>6</Month>
<Day>23</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez"><Year>2019</Year>
<Month>6</Month>
<Day>28</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList><ArticleId IdType="pubmed">31244112</ArticleId>
<ArticleId IdType="doi">10.1021/acs.jmedchem.9b00525</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations><list><country><li>Canada</li>
<li>Suisse</li>
</country>
</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="Keles, Erhan" sort="Keles, Erhan" uniqKey="Keles E" first="Erhan" last="Keles">Erhan Keles</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="Sriramaratnam, Rohitha" sort="Sriramaratnam, Rohitha" uniqKey="Sriramaratnam R" first="Rohitha" last="Sriramaratnam">Rohitha Sriramaratnam</name>
<name sortKey="Wymann, Matthias P" sort="Wymann, Matthias P" uniqKey="Wymann M" first="Matthias P" last="Wymann">Matthias P. Wymann</name>
</country>
<country name="Canada"><noRegion><name sortKey="Mcphail, Jacob A" sort="Mcphail, Jacob A" uniqKey="Mcphail J" first="Jacob A" last="Mcphail">Jacob A. Mcphail</name>
</noRegion>
<name sortKey="Burke, John E" sort="Burke, John E" uniqKey="Burke J" first="John E" last="Burke">John E. Burke</name>
<name sortKey="Hoffmann, Reece M" sort="Hoffmann, Reece M" uniqKey="Hoffmann R" first="Reece M" last="Hoffmann">Reece M. Hoffmann</name>
</country>
</tree>
</affiliations>
</record>

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   |texte=   (S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.
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(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

(S)-4-(Difluoromethyl)-5-(4-(3-methylmorpholino)-6-morpholino-1,3,5-triazin-2-yl)pyridin-2-amine (PQR530), a Potent, Orally Bioavailable, and Brain-Penetrable Dual Inhibitor of Class I PI3K and mTOR Kinase.

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