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 F Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Cmiljanovic N Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Cmiljanovic V Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Bohnacker T Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Melone A Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Marone R Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Jackson E Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Zhang X MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, U.K.
- Sele A Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Borsari C Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Mestan J PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland.
- Hebeisen P PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland.
- Hillmann P PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland.
- Giese B Department of Chemistry, University of Basel , St. Johanns-Ring 19, 4056 Basel, Switzerland.
- Zvelebil M Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Fabbro D PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland.
- Williams RL MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, U.K.
- Rageot D Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- Wymann MP Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland.
- 2017-08-23
Published in:
- Journal of medicinal chemistry. - 2017
Administration, Oral
Aminopyridines
Animals
Antineoplastic Agents
Brain
Cell Proliferation
Dogs
Humans
Mice
Models, Molecular
Morpholines
Neoplasms
Phosphatidylinositol 3-Kinases
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Rats
Rats, Nude
Signal Transduction
TOR Serine-Threonine Kinases
English
Phosphoinositide 3-kinase (PI3K) is deregulated in a wide variety of human tumors and triggers activation of protein kinase B (PKB/Akt) and mammalian target of rapamycin (mTOR). Here we describe the preclinical characterization of compound 1 (PQR309, bimiralisib), a potent 4,6-dimorpholino-1,3,5-triazine-based pan-class I PI3K inhibitor, which targets mTOR kinase in a balanced fashion at higher concentrations. No off-target interactions were detected for 1 in a wide panel of protein kinase, enzyme, and receptor ligand assays. Moreover, 1 did not bind tubulin, which was observed for the structurally related 4 (BKM120, buparlisib). Compound 1 is orally available, crosses the blood-brain barrier, and displayed favorable pharmacokinetic parameters in mice, rats, and dogs. Compound 1 demonstrated efficiency in inhibiting proliferation in tumor cell lines and a rat xenograft model. This, together with the compound's safety profile, identifies 1 as a clinical candidate with a broad application range in oncology, including treatment of brain tumors or CNS metastasis. Compound 1 is currently in phase II clinical trials for advanced solid tumors and refractory lymphoma.
- Language
-
- English
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1021/acs.jmedchem.7b00930
- PMID 28829592
- Persistent URL
- https://sonar.ch/global/documents/51397
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