关键词： Antiproliferative Apoptosis Non Hodgkin's lymphoma PI3Kδ inhibitor Piperazinone Purine

Mesh ： Animals Antineoplastic Agents / chemical synthesis pharmacology Cell Line, Tumor Cell Proliferation / drug effects Drug Design Enzyme Inhibitors / chemical synthesis pharmacology Heterografts Humans Lymphoma, Non-Hodgkin / drug therapy Mice, SCID Mitogen-Activated Protein Kinase Kinases / metabolism Molecular Docking Simulation Morpholines / chemistry Neoplasms, Experimental Phosphatidylinositol 3-Kinases / metabolism Phosphorylation Piperazines / chemistry Purines / chemical synthesis pharmacology

来  源：   DOI：10.1016/j.bioorg.2020.104344   PDF(Sci-hub)

Abstract：
PI3Kδ has proved to be an effective target for anti-lymphoma drugs. However, the application of current approved PI3Kδ inhibitors has been greatly limited due to their specific immune-mediated toxicity and increased risk of infection, it is necessary to develop more PI3Kδ inhibitors with new scaffold. In this study, SAR study with respect to piperazinone-containing purine derivatives led to the discovery of a potent and selective PI3Kδ inhibitor, 4-(cyclobutanecarbonyl)-1-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-2-one (WNY1613). WNY1613 exhibits good antiproliferative activity against a panel of non-Hodgkin\'s lymphoma (NHL) cell lines by inducing cancer cell apoptosis and inhibiting the phosphorylation of PI3K and MAPK downstream components. In addition, it can also prevent the tumor growth in both SU-DHL-6 and JEKO-1 xenograft models without observable toxicity. WNY1613 thus could be developed as a promising candidate for the treatment of NHL after subsequent extensive pharmacodynamics and pharmacokinetics investigation.
摘要：
暂无翻译
公众号