SNSF | P3 Research Database

English title	Targeting PI3K Interactions in Disease
Applicant	Wymann Matthias
Number	153211
Funding scheme	Project funding
Research institution	Institut für Biochemie und Genetik Universität Basel
Institution of higher education	University of Basel - BS
Main discipline	Biochemistry
Start/End	01.01.2015 - 31.03.2019
Approved amount	525'000.00

Discipline

Biochemistry

Immunology, Immunopathology

Experimental Cancer Research

DNA repair; Phosphoinositide 3-kinase; Mast cells; Allergy; Cancer; Inflammation; PI3K; protein-protein interaction

Lead
Die Zusammensetzung von Zellmembranen bestimmt Verhalten und Schicksal der Zellen unseres Körpers. Sogenannte Lipid Kinasen - wie die Phosphoinositide 3-Kinase (PI3K) - verändern die Lipidschicht auf der Innenseite der Zelle, wenn sie durch Wachstumsfaktor-Rezeptoren stimuliert werden. Durch die PI3K wird so auf der Zellmembran eine Erkennungsstelle für weitere Signalenzyme gebildet. Die durch die PI3K ausgelösten Signalkaskaden sind nach heutiger Erkenntnis wichtig in Krebsbildung, chronischer Entzündung, Autoimmun-Krankheiten, Allergien, metabolischen Krankheiten und Herz/Kreislauferkrankungen. Mutationen in PI3K oder die übermässige Aktivierung derselben durch mutierte Wachstumsfaktor-Rezeptoren führen zu unkontrolliertem Zellwachstum, Zellteilung, bösartiger Zellwanderung und zum Überleben von Zellen in einem falschen Gewebskontext.
Lay summary
Zur Zeit werden grosse Anstrengungen unternommen, um Inhibitoren zur therapeutischen Kontrolle der PI3K Aktivität zu entwickeln. PI3K verbraucht als Energieträger ein Molekül ATP, um ein aktives Lipidmolekül (PtdIns(3,4,5)P₃ oder kurz PIP3) zu produzieren. Deshalb wird gegenwärtig die Bindungsstelle von ATP blockiert, damit PI3K in verschiedenen Krankheiten kontrolliert werden kann. Viele Aspekte der PI3K Aktivierung sind noch nicht aufgeklärt: so werden immer wieder neue, unerwartete Aktivierungsmodi und Rückkoppelungsschlafen entdeckt, und die Wirkung von PIP3 scheint abhängig von seiner Lokalisierung in Mikrodomänen der Zellmembran zu sein. Hier wollen wir neue regulatorische Mechanismen und mit PI3K interagierende Proteine identifizieren, welche die Aktivität und die Signalwirkung von zwei PI3K Komplexen, der PI3Kalfa und der PI3Kgamma, beeinflussen. Die katalytische Untereinheit der PI3Kalfa ist in Krebszellen häufig mutiert, was zur Erhöhung der PIP3 Konzentration und dem Überleben von Krebszellen führt. Erste Resultate deuten hier auf eine neue Verknüpfung von PI3Kalfa und DNA Reparaturprozessen hin. PI3Kgamma arbeitet unterhalb von Rezeptoren, die ihre Signale an sogenannte „trimerische“ G Proteine weitergeben. Diese binden direkt an den PI3Kgamma Komplex, welcher aus einer katalytischen p110gamma Untereinheit und einem Adaptorprotein vom Typ p84 oder p101 besteht. Die Zusammensetzung des PI3Kgamma Komplexes scheint die folgende Zellantwort und die Lokalisierung des PIP3 in der Zellmembran zu bestimmen. Insgesamt sollen die geplanten Versuche dazu beitragen, die Konsequenzen einer Deregulation von PI3K in entzündlichen und proliferativen Krankheiten besser zu verstehen und zu kontrollieren.

Lead

Die Zusammensetzung von Zellmembranen bestimmt Verhalten und Schicksal der Zellen unseres Körpers. Sogenannte Lipid Kinasen - wie die Phosphoinositide 3-Kinase (PI3K) - verändern die Lipidschicht auf der Innenseite der Zelle, wenn sie durch Wachstumsfaktor-Rezeptoren stimuliert werden. Durch die PI3K wird so auf der Zellmembran eine Erkennungsstelle für weitere Signalenzyme gebildet. Die durch die PI3K ausgelösten Signalkaskaden sind nach heutiger Erkenntnis wichtig in Krebsbildung, chronischer Entzündung, Autoimmun-Krankheiten, Allergien, metabolischen Krankheiten und Herz/Kreislauferkrankungen. Mutationen in PI3K oder die übermässige Aktivierung derselben durch mutierte Wachstumsfaktor-Rezeptoren führen zu unkontrolliertem Zellwachstum, Zellteilung, bösartiger Zellwanderung und zum Überleben von Zellen in einem falschen Gewebskontext.

Lay summary

Zur Zeit werden grosse Anstrengungen unternommen, um Inhibitoren zur therapeutischen Kontrolle der PI3K Aktivität zu entwickeln. PI3K verbraucht als Energieträger ein Molekül ATP, um ein aktives Lipidmolekül (PtdIns(3,4,5)P₃ oder kurz PIP3) zu produzieren. Deshalb wird gegenwärtig die Bindungsstelle von ATP blockiert, damit PI3K in verschiedenen Krankheiten kontrolliert werden kann.

Viele Aspekte der PI3K Aktivierung sind noch nicht aufgeklärt: so werden immer wieder neue, unerwartete Aktivierungsmodi und Rückkoppelungsschlafen entdeckt, und die Wirkung von PIP3 scheint abhängig von seiner Lokalisierung in Mikrodomänen der Zellmembran zu sein.

Hier wollen wir neue regulatorische Mechanismen und mit PI3K interagierende Proteine identifizieren, welche die Aktivität und die Signalwirkung von zwei PI3K Komplexen, der PI3Kalfa und der PI3Kgamma, beeinflussen. Die katalytische Untereinheit der PI3Kalfa ist in Krebszellen häufig mutiert, was zur Erhöhung der PIP3 Konzentration und dem Überleben von Krebszellen führt. Erste Resultate deuten hier auf eine neue Verknüpfung von PI3Kalfa und DNA Reparaturprozessen hin.

PI3Kgamma arbeitet unterhalb von Rezeptoren, die ihre Signale an sogenannte „trimerische“ G Proteine weitergeben. Diese binden direkt an den PI3Kgamma Komplex, welcher aus einer katalytischen p110gamma Untereinheit und einem Adaptorprotein vom Typ p84 oder p101 besteht. Die Zusammensetzung des PI3Kgamma Komplexes scheint die folgende Zellantwort und die Lokalisierung des PIP3 in der Zellmembran zu bestimmen.

Insgesamt sollen die geplanten Versuche dazu beitragen, die Konsequenzen einer Deregulation von PI3K in entzündlichen und proliferativen Krankheiten besser zu verstehen und zu kontrollieren.

Direct link to Lay Summary

Last update: 29.01.2015

Lead
The composition of cell membranes influences a cell’s fate, and determines the activity of intracellular signaling events. Lipid kinases such as the phosphoinositide 3-kinase (PI3K) change the inner leaflet of the plasma membrane after their stimulation by cell surface receptors. This creates docking sites for signaling molecules and complexes at the membrane, where inflammatory and oncogenic signals can originate. The current understanding of PI3K signaling links this lipid kinase to processes promoting cancer, chronic inflammation, allergy, metabolic disease and cardiovascular events. Mutations in PI3K, or its over-activation by growth factor receptor-linked signaling leads to sustained cell growth, cell cycle entry, cell migration and cell survival.
Lay summary
Presently, major efforts to produce inhibitors for PI3K enzyme are in progress. As PI3K utilizes ATP to phosphorylate the membrane lipid PtdIns(4,5)P₂ (short PIP2) to produce PtdIns(3,4,5)P₃ (PIP3), the ATP-binding pocket of PI3K is a common target for small molecules modulating PI3K-dependent disease. Many aspects of PI3K activation are, however, currently not fully understood. There are unexpected and non-dogmatic inputs and feedback loops activating PI3K, and specifically localized pools of the PI3K product PIP3 seem to result in distinct and non-redundant signals and cell responses. Here we aim to elucidate novel regulatory mechanisms and interacting proteins that control the activity and output of the PI3Kalfa and PI3Kgamma complexes. The catalytic subunit of PI3Kalfa is frequently mutated in cancer, which leads to elevation of PIP3 levels – which is key to cancer cell survival. For PI3Kalfa we will investigate a missing link between PI3Kalfa and DNA-repair processes. PI3Kgamma operates downstream of G protein-coupled receptors (GPCRs), and is directly activated by beta/gamma subunits of trimeric G proteins. PI3Kgamma is composed of a catalytic p110gamma subunit, and an adapter subunit, which is either p84 or p101. We have recently shown that p110gamma can be modified by a protein kinase called PKCbeta. In the main cell promoting allergic reactions – the mast cell – PKCbeta can phosphorylate and activate p110gamma. Present studies suggest that phosphorylation and cell-specific composition of the PI3Kgamma complex determines its coupling to GPCRs.

Lead

The composition of cell membranes influences a cell’s fate, and determines the activity of intracellular signaling events. Lipid kinases such as the phosphoinositide 3-kinase (PI3K) change the inner leaflet of the plasma membrane after their stimulation by cell surface receptors. This creates docking sites for signaling molecules and complexes at the membrane, where inflammatory and oncogenic signals can originate. The current understanding of PI3K signaling links this lipid kinase to processes promoting cancer, chronic inflammation, allergy, metabolic disease and cardiovascular events. Mutations in PI3K, or its over-activation by growth factor receptor-linked signaling leads to sustained cell growth, cell cycle entry, cell migration and cell survival.

Lay summary

Presently, major efforts to produce inhibitors for PI3K enzyme are in progress. As PI3K utilizes ATP to phosphorylate the membrane lipid PtdIns(4,5)P₂ (short PIP2) to produce PtdIns(3,4,5)P₃ (PIP3), the ATP-binding pocket of PI3K is a common target for small molecules modulating PI3K-dependent disease. Many aspects of PI3K activation are, however, currently not fully understood. There are unexpected and non-dogmatic inputs and feedback loops activating PI3K, and specifically localized pools of the PI3K product PIP3 seem to result in distinct and non-redundant signals and cell responses.

Here we aim to elucidate novel regulatory mechanisms and interacting proteins that control the activity and output of the PI3Kalfa and PI3Kgamma complexes. The catalytic subunit of PI3Kalfa is frequently mutated in cancer, which leads to elevation of PIP3 levels – which is key to cancer cell survival. For PI3Kalfa we will investigate a missing link between PI3Kalfa and DNA-repair processes.

PI3Kgamma operates downstream of G protein-coupled receptors (GPCRs), and is directly activated by beta/gamma subunits of trimeric G proteins. PI3Kgamma is composed of a catalytic p110gamma subunit, and an adapter subunit, which is either p84 or p101. We have recently shown that p110gamma can be modified by a protein kinase called PKCbeta. In the main cell promoting allergic reactions – the mast cell – PKCbeta can phosphorylate and activate p110gamma. Present studies suggest that phosphorylation and cell-specific composition of the PI3Kgamma complex determines its coupling to GPCRs.

Direct link to Lay Summary

Last update: 29.01.2015

Name	Institute

Wymann Matthias

Departement Biomedizin Universität Basel

Name	Institute

Da Costa Xavier Ana Ricardo

Zentrum für Biomedizin Dept. Klinisch-Biologische Wissenschaften Universität Basel

Publication

Brain-penetrant PQR620 mTOR and PQR530 PI3K/mTOR inhibitor reduce huntingtin levels in cell models of HD

Singer Elisabeth, Walter Carolin, Fabbro Doriano, Rageot Denise, Beaufils Florent, Wymann Matthias P., Rischert Nadine, Riess Olaf, Hillmann Petra, Nguyen Huu Phuc (2020), Brain-penetrant PQR620 mTOR and PQR530 PI3K/mTOR inhibitor reduce huntingtin levels in cell models of HD, in Neuropharmacology, 162, 107812-107812.

Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology

Takeda Andrew J., Maher Timothy J., Zhang Yu, Lanahan Stephen M., Bucklin Molly L., Compton Susan R., Tyler Paul M., Comrie William A., Matsuda Makoto, Olivier Kenneth N., Pittaluga Stefania, McElwee Joshua J., Long Priel Debra A., Kuhns Douglas B., Williams Roger L., Mustillo Peter J., Wymann Matthias P., Koneti Rao V., Lucas Carrie L. (2019), Human PI3Kγ deficiency and its microbiota-dependent mouse model reveal immunodeficiency and tissue immunopathology, in Nature Communications, 10(1), 4364-4364.

Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl–Pyrimidine Moiety

Borsari Chiara, Rageot Denise, Beaufils Florent, Bohnacker Thomas, Keles Erhan, Buslov Ivan, Melone Anna, Sele Alexander M., Hebeisen Paul, Fabbro Doriano, Hillmann Petra, Wymann Matthias P. (2019), Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl–Pyrimidine Moiety, in ACS Medicinal Chemistry Letters, 10(10), 1473-1479.

A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor

Borsari Chiara, Rageot Denise, Dall’Asen Alix, Bohnacker Thomas, Melone Anna, Sele Alexander M., Jackson Eileen, Langlois Jean-Baptiste, Beaufils Florent, Hebeisen Paul, Fabbro Doriano, Hillmann Petra, Wymann Matthias P. (2019), A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor, in Journal of Medicinal Chemistry, 62(18), 8609-8630.

( 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

Rageot Denise, Bohnacker Thomas, Keles Erhan, McPhail Jacob A., Hoffmann Reece M., Melone Anna, Borsari Chiara, Sriramaratnam Rohitha, Sele Alexander M., Beaufils Florent, Hebeisen Paul, Fabbro Doriano, Hillmann Petra, Burke John E., Wymann Matthias P. (2019), ( 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, in Journal of Medicinal Chemistry, 62(13), 6241-6261.

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax

Tarantelli Chiara, Gaudio Eugenio, Hillmann Petra, Spriano Filippo, Sartori Giulio, Aresu Luca, Cascione Luciano, Rageot Denise, Kwee Ivo, Beaufils Florent, Zucca Emanuele, Stathis Anastasios, Wymann Matthias P., Cmiljanovic Vladimir, Fabbro Doriano, Bertoni Francesco (2019), The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax, in Cancers, 11(6), 775-775.

New molecular and therapeutic insights into canine diffuse large B-cell lymphoma elucidates the role of the dog as a model for human disease

Aresu Luca, Ferraresso Serena, Marconato Laura, Cascione Luciano, Napoli Sara, Gaudio Eugenio, Kwee Ivo, Tarantelli Chiara, Testa Andrea, Maniaci Chiara, Ciulli Alessio, Hillmann Petra, Bohnacker Thomas, Wymann Matthias P., Comazzi Stefano, Milan Massimo, Riondato Fulvio, Rovere Giulia Dalla, Giantin Mery, Giannuzzi Diana, Bertoni Francesco (2019), New molecular and therapeutic insights into canine diffuse large B-cell lymphoma elucidates the role of the dog as a model for human disease, in Haematologica, 104(6), e256-e259.

New molecular and therapeutic insights into canine diffuse large B-cell lymphoma elucidates the role of the dog as a model for human disease

Aresu Luca, Ferraresso Serena, Marconato Laura, Cascione Luciano, Napoli Sara, Gaudio Eugenio, Kwee Ivo, Tarantelli Chiara, Testa Andrea, Maniaci Chiara, Ciulli Alessio, Hillmann Petra, Bohnacker Thomas, Wymann Matthias P., Comazzi Stefano, Milan Massimo, Riondato Fulvio, Rovere Giulia Dalla, Giantin Mery, Giannuzzi Diana, Bertoni Francesco (2019), New molecular and therapeutic insights into canine diffuse large B-cell lymphoma elucidates the role of the dog as a model for human disease, in Haematologica, 104(6), e256-e259.

A class of highly selective inhibitors bind to an active state of PI3Kγ

Gangadhara Gangadhara, Dahl Göran, Bohnacker Thomas, Rae Rebecca, Gunnarsson Jenny, Blaho Stefan, Öster Linda, Lindmark Helena, Karabelas Kostas, Pemberton Nils, Tyrchan Christian, Mogemark Mickael, Wymann Matthias P., Williams Roger L., Perry Matthew W. D., Papavoine Tineke, Petersen Jens (2019), A class of highly selective inhibitors bind to an active state of PI3Kγ, in Nature Chemical Biology, 15(4), 348-357.

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

Rageot Denise, Bohnacker Thomas, Melone Anna, Langlois Jean-Baptiste, Borsari Chiara, Hillmann Petra, Sele Alexander M., Beaufils Florent, Zvelebil Marketa, Hebeisen Paul, Löscher Wolfgang, Burke John, Fabbro Doriano, Wymann Matthias P. (2018), 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, in Journal of Medicinal Chemistry, 61(22), 10084-10105.

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

Rageot Denise, Bohnacker Thomas, Melone Anna, Langlois Jean-Baptiste, Borsari Chiara, Hillmann Petra, Sele Alexander M., Beaufils Florent, Zvelebil Marketa, Hebeisen Paul, Löscher Wolfgang, Burke John, Fabbro Doriano, Wymann Matthias P. (2018), 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, in Journal of Medicinal Chemistry, 61(22), 10084-10105.

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

Rageot Denise, Bohnacker Thomas, Melone Anna, Langlois Jean-Baptiste, Borsari Chiara, Hillmann Petra, Sele Alexander M., Beaufils Florent, Zvelebil Marketa, Hebeisen Paul, Löscher Wolfgang, Burke John, Fabbro Doriano, Wymann Matthias P. (2018), 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, in Journal of Medicinal Chemistry, 61(22), 10084-10105.

The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy

Brandt Claudia, Hillmann Petra, Noack Andreas, Römermann Kerstin, Öhler Leon A., Rageot Denise, Beaufils Florent, Melone Anna, Sele Alexander M., Wymann Matthias P., Fabbro Doriano, Löscher Wolfgang (2018), The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy, in Neuropharmacology, 140, 107-120.

PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy

Tarantelli Chiara, Gaudio Eugenio, Arribas Alberto J., Kwee Ivo, Hillmann Petra, Rinaldi Andrea, Cascione Luciano, Spriano Filippo, Bernasconi Elena, Guidetti Francesca, Carrassa Laura, Pittau Roberta Bordone, Beaufils Florent, Ritschard Reto, Rageot Denise, Sele Alexander, Dossena Barbara, Rossi Francesca Maria, Zucchetto Antonella, Taborelli Monica, Gattei Valter, Rossi Davide, Stathis Anastasios, Stussi Georg, et al. (2018), PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy, in Clinical Cancer Research, 24(1), 120-129.

Central role for phosphoinositide-3-kinase gamma/delta dependent signalling in eosinophilic pulmonary inflammation driven by innate lymphoid cells

Thomas Matt, Bjorhall Karin, Collins Mia, Israelsson Elisabeth, Krutrok Nina, LammBergstrom Eva, Maciewicz Rose, Muthas Daniel, Nordberg Maria, Perry Matthew, RodrigoBlomqvist Sandra, Saarne Tiiu, Winkler Carla, Karabelas Kostas, Malmgren Anna, Adcock Ian, Chung Fan, Wymann Matthias (2017), Central role for phosphoinositide-3-kinase gamma/delta dependent signalling in eosinophilic pulmonary inflammation driven by innate lymphoid cells, in ERS International Congress 2017 abstracts, Sheffield European Respiratory Journal, Sheffield, UK.

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

Beaufils Florent, Cmiljanovic Natasa, Cmiljanovic Vladimir, Bohnacker Thomas, Melone Anna, Marone Romina, Jackson Eileen, Zhang Xuxiao, Sele Alexander, Borsari Chiara, Mestan Jürgen, Hebeisen Paul, Hillmann Petra, Giese Bernd, Zvelebil Marketa, Fabbro Doriano, Williams Roger L., Rageot Denise, Wymann Matthias P. (2017), 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology, in Journal of Medicinal Chemistry, 60(17), 7524-7538.

5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology

Beaufils Florent, Cmiljanovic Natasa, Cmiljanovic Vladimir, Bohnacker Thomas, Melone Anna, Marone Romina, Jackson Eileen, Zhang Xuxiao, Sele Alexander, Borsari Chiara, Mestan Jürgen, Hebeisen Paul, Hillmann Petra, Giese Bernd, Zvelebil Marketa, Fabbro Doriano, Williams Roger L., Rageot Denise, Wymann Matthias P. (2017), 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology, in Journal of Medicinal Chemistry, 60(17), 7524-7538.

PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity

Breasson Ludovic, Becattini Barbara, Sardi Claudia, Molinaro Angela, Zani Fabio, Marone Romina, Botindari Fabrizio, Bousquenaud Mélanie, Ruegg Curzio, Wymann Matthias P., Solinas Giovanni (2017), PI3Kγ activity in leukocytes promotes adipose tissue inflammation and early-onset insulin resistance during obesity, in Science Signaling, 10(488), eaaf2969-eaaf2969.

Abstract 140: Discovery and biological evaluation of PQR530, a highly potent dual pan-PI3K/mTORC1/2 inhibitor

Rageot Denise, Beaufils Florent, Melone Anna, Sele Alexander M., Bohnacker Thomas, Lang Marc, Mestan Jürgen, Hillmann Petra, Hebeisen Paul, Fabbro Doriano, Wymann Matthias P. (2017), Abstract 140: Discovery and biological evaluation of PQR530, a highly potent dual pan-PI3K/mTORC1/2 inhibitor, in Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC, American Association for Cancer Research., Boston.

Abstract 153: Tricyclic fused pyrimidinopyrrolo-oxazines reveal conformational preferences of morpholine for PI3K hinge region binding

Sele Alexander M., Rageot Denise, Beaufils Florent, Melone Anna, Bohnacker Thomas, Jackson Eileen, Langlois Jean-Baptiste, Hebeisen Paul, Fabbro Doriano, Wymann Matthias P. (2017), Abstract 153: Tricyclic fused pyrimidinopyrrolo-oxazines reveal conformational preferences of morpholine for PI3K hinge region binding, in Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC, CancerRessearch, Washington DC.

Abstract 159: Pharmacological characterization of the selective, orally bioavailable, potent dual PI3K/mTORC1/2 inhibitor PQR530

Hillmann Petra, Rageot Denise, Beaufils Florent, Melone Anna, Sele Alexander, Ettlin Robert A., Mestan Jürgen, Cmiljanovic Vladimir, Lang Marc, Singer Elisabeth, Walter Carolin, Nguyen Hoa HP, Hebeisen Paul, Wymann Matthias P., Fabbro Doriano (2017), Abstract 159: Pharmacological characterization of the selective, orally bioavailable, potent dual PI3K/mTORC1/2 inhibitor PQR530, in Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC, American Association for Cancer Research., Boston.

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

Bohnacker Thomas, Prota Andrea E., Beaufils Florent, Burke John E., Melone Anna, Inglis Alison J., Rageot Denise, Sele Alexander M., Cmiljanovic Vladimir, Cmiljanovic Natasa, Bargsten Katja, Aher Amol, Akhmanova Anna, Díaz J. Fernando, Fabbro Doriano, Zvelebil Marketa, Williams Roger L., Steinmetz Michel O., Wymann Matthias P. (2017), Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention, in Nature Communications, 8(1), 14683-14683.

Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention

Bohnacker Thomas, Prota Andrea E., Beaufils Florent, Burke John E., Melone Anna, Inglis Alison J., Rageot Denise, Sele Alexander M., Cmiljanovic Vladimir, Cmiljanovic Natasa, Bargsten Katja, Aher Amol, Akhmanova Anna, Díaz J. Fernando, Fabbro Doriano, Zvelebil Marketa, Williams Roger L., Steinmetz Michel O., Wymann Matthias P. (2017), Deconvolution of Buparlisib’s mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention, in Nature Communications, 8(1), 14683-14683.

Abstract 1336: Structure-activity relationship studies, synthesis, and biological evaluation of PQR620, a highly potent and selective mTORC1/2 inhibitor

Beaufils Florent, Rageot Denise, Melone Anna, Lang Marc, Mestan Jürgen, Cmiljanovic Vladimir, Hillmann Petra, Hebeisen Paul, Fabbro Doriano, Wymann Matthias P. (2016), Abstract 1336: Structure-activity relationship studies, synthesis, and biological evaluation of PQR620, a highly potent and selective mTORC1/2 inhibitor, in Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA, 76, 1336.

Abstract 1364: Novel 4-(pyrimidin-2-yl)morpholines targeting the colchicine-binding site of tubulin

Sele Alexander M., Rageot Denise, Bohnacker Thomas, Beaufils Florent, Prota Andrea E., Steinmetz Michel O., Wymann Matthias P. (2016), Abstract 1364: Novel 4-(pyrimidin-2-yl)morpholines targeting the colchicine-binding site of tubulin, in Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA, CancerRessearch, Washington DC.

Abstract 393A: Pharmacological characterization of the selective, orally bioavailable, potent mTORC1/2 inhibitor PQR620

Beaufils Florent, Rageot Denise, Melone Anna, Sele Alexander, Lang Marc, Mestan Juergen, Ettlin Robert A., Hillmann Petra, Cmiljanovic Vladimir, Walter Carolin, Singer Elisabeth, Nguyen Hoa HP, Hebeisen Paul, Fabbro Doriano, Wymann Matthias P. (2016), Abstract 393A: Pharmacological characterization of the selective, orally bioavailable, potent mTORC1/2 inhibitor PQR620, in Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA, CancerRessearch, Boston.

Abstract 2652: Pre-clinical activity and mechanism of action of the novel dual PI3K/mTOR inhibitor PQR309 in B-cell lymphomas

Tarantelli Chiara, Gaudio Eugenio, Kwee Ivo, Rinaldi Andrea, Bernasconi Elena, Cascione Luciano, Hillmann Petra, Stathis Anastasios, Carrassa Laura, Broggini Massimo, Stussi Georg, Fabbro Doriano, Beaufils Florent, Melone Anna, Bohnacker Thomas, Wymann Matthias P., Wicki Andreas, Zucca Emanuele, Cmiljanovic Vladimir, Bertoni Francesco (2015), Abstract 2652: Pre-clinical activity and mechanism of action of the novel dual PI3K/mTOR inhibitor PQR309 in B-cell lymphomas, in Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA, American Association for Cancer Research., Boston.

Abstract 671: BKM120-mediated G2 arrest: Structural and functional segregation of off-target action and PI3K inhibition

Bohnacker Thomas, Beaufils Florent, Prota Andrea E., Burke John E., Melone Anna, Inglis Alison J., Fusco Ludovico, Cmiljanovic Vladimir, Cmiljanovic Natasa, Rageot Denise, Bargsten Katja, Saez-Calvo Gonzalo, Pertz Olivier, Aher Amol B., Akhmanova Anna, Diaz Fernando J., Fabbro Doriano, Zvelebil Marketa, Williams Roger L., Steinmetz Michel O., Wymann Matthias P. (2015), Abstract 671: BKM120-mediated G2 arrest: Structural and functional segregation of off-target action and PI3K inhibition, in Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA, American Association for Cancer Research., Boston.

Group / person	Country

	Types of collaboration

University of Victoria

Canada (North America)