Discovery of 2-ureidophenyltriazines bearing bridged morpholines as potent and selective ATP-competitive mTOR inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 8; pp. 2644 - 2647
• Main Authors: Zask, Arie, Verheijen, Jeroen C., Richard, David J., Kaplan, Joshua, Curran, Kevin, Toral-Barza, Lourdes, Lucas, Judy, Hollander, Irwin, Yu, Ker
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-04-2010; Elsevier
• Subjects: Adenosine Triphosphate - chemistry; Animals; Antineoplastic agents; Antiproliferative; Biological and medical sciences; Cancer; Drug Discovery; General aspects; Inhibitor; Inhibitory Concentration 50; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Kinase; Medical sciences; Mice; Mice, Nude; Morpholines - chemistry; mTOR; Oncology; Pharmacology. Drug treatments; PI3K; Protein-Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases; Triazines - chemistry; Triazines - pharmacology; Antiproliferative; PI3K; Kinase; mTOR; Oncology; Inhibitor; Cancer; Antineoplastic agent; Intravenous administration; Nitrogen heterocycle; Non-specific serine/threonine protein kinase; Glioblastoma; Cytotoxicity; Selectivity; Malignant glioma; Signal transduction; Structure activity relation; Six membered ring; Bicyclic compound; Mammary gland; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Malignant tumor; Epithelium; In vitro; 1-Phosphatidylinositol 3-kinase; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Cell line; Mouse; Animal; Triazine derivatives; Mammalian target of rapamycin; Piperazine derivatives; P13K
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.045

Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs leading to compounds which suppressed mTOR biomarkers in vivo and possessed excellent efficacy in a murine xenograft model.
Incorporation of bridged morpholines in monocyclic triazine PI3K/mTOR inhibitors gave compounds with increased mTOR selectivity relative to the corresponding morpholine analogs. Compounds with ureidophenyl groups gave highly potent and selective mTOR inhibitors. Potency and selectivity was demonstrated both in vitro and in vivo through biomarker suppression studies. Select compounds exhibited potent inhibition of tumor growth in nude mouse xenograft assays upon PO and IV administration.