Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.
作者： Aranapakam M. Venkatesan , Christoph M. Dehnhardt , Efren Delos Santos , Zecheng Chen , Osvaldo Dos Santos
DOI: 10.1021/JM901830P
关键词: Phosphatidylinositol 、 TOR Serine-Threonine Kinases 、 In vivo 、 Kinase 、 PI3K/AKT/mTOR pathway 、 Structure–activity relationship 、 In vitro 、 Akt/PKB signaling pathway 、 Biochemistry 、 Chemistry 、 Pharmacology
摘要: The PI3K/Akt signaling pathway is a key in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this might provide viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared optimized to the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound shown excellent activity vitro vivo, with antitumor efficacy both subcutaneous orthotopic xenograft tumor models when administered intravenously. structure−activity relationships vivo analogues are described.
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