PMID- 28829592 OWN - NLM STAT- MEDLINE DCOM- 20170926 LR - 20220129 IS - 1520-4804 (Electronic) IS - 0022-2623 (Print) IS - 0022-2623 (Linking) VI - 60 IP - 17 DP - 2017 Sep 14 TI - 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. PG - 7524-7538 LID - 10.1021/acs.jmedchem.7b00930 [doi] AB - 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. FAU - Beaufils, Florent AU - Beaufils F AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Cmiljanovic, Natasa AU - Cmiljanovic N AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Cmiljanovic, Vladimir AU - Cmiljanovic V AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Bohnacker, Thomas AU - Bohnacker T AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Melone, Anna AU - Melone A AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Marone, Romina AU - Marone R AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Jackson, Eileen AU - Jackson E AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Zhang, Xuxiao AU - Zhang X AD - MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, U.K. FAU - Sele, Alexander AU - Sele A AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Borsari, Chiara AU - Borsari C AUID- ORCID: 0000-0002-4688-8362 AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Mestan, Jurgen AU - Mestan J AD - PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland. FAU - Hebeisen, Paul AU - Hebeisen P AD - PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland. FAU - Hillmann, Petra AU - Hillmann P AD - PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland. FAU - Giese, Bernd AU - Giese B AD - Department of Chemistry, University of Basel , St. Johanns-Ring 19, 4056 Basel, Switzerland. FAU - Zvelebil, Marketa AU - Zvelebil M AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Fabbro, Doriano AU - Fabbro D AD - PIQUR Therapeutics AG , Hochbergerstrasse 60C, 4057 Basel, Switzerland. FAU - Williams, Roger L AU - Williams RL AD - MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, U.K. FAU - Rageot, Denise AU - Rageot D AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. FAU - Wymann, Matthias P AU - Wymann MP AUID- ORCID: 0000-0003-3349-4281 AD - Department of Biomedicine, University of Basel , Mattenstrasse 28, 4058 Basel, Switzerland. LA - eng GR - MC_U105184308/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20170901 PL - United States TA - J Med Chem JT - Journal of medicinal chemistry JID - 9716531 RN - 0 (Aminopyridines) RN - 0 (Antineoplastic Agents) RN - 0 (Morpholines) RN - 0 (NVP-BKM120) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Administration, Oral MH - Aminopyridines/administration & dosage/pharmacokinetics/*therapeutic use MH - Animals MH - Antineoplastic Agents/administration & dosage/pharmacokinetics/*therapeutic use MH - Brain/drug effects/metabolism MH - Cell Proliferation/drug effects MH - Dogs MH - Humans MH - Mice MH - Models, Molecular MH - Morpholines/administration & dosage/pharmacokinetics/*therapeutic use MH - Neoplasms/*drug therapy/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - *Phosphoinositide-3 Kinase Inhibitors MH - Protein Kinase Inhibitors/administration & dosage/pharmacokinetics/*therapeutic use MH - Rats MH - Rats, Nude MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism PMC - PMC5656176 MID - EMS74491 COIS- Notes The authors declare the following competing financial interest(s): F.B., N.C., V.C., J.M., P.He., P.Hi., and D.F. are current or past employees of PIQUR Therapeutics AG, Basel; and N.C., V.C., J.M., P.He., P.Hi., D.F., B.G., and M.P.W. are shareholders of PIQUR Therapeutics AG. EDAT- 2017/08/23 06:00 MHDA- 2017/09/28 06:00 PMCR- 2017/10/25 CRDT- 2017/08/23 06:00 PHST- 2017/08/23 06:00 [pubmed] PHST- 2017/09/28 06:00 [medline] PHST- 2017/08/23 06:00 [entrez] PHST- 2017/10/25 00:00 [pmc-release] AID - 10.1021/acs.jmedchem.7b00930 [doi] PST - ppublish SO - J Med Chem. 2017 Sep 14;60(17):7524-7538. doi: 10.1021/acs.jmedchem.7b00930. Epub 2017 Sep 1.