Design, Synthesis, and Biological Activity of Pyridopyrimidine Scaffolds as Novel PI3K/mTOR Dual Inhibitors

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• 作者：Thibault Saurat ; Frédéric Buron ; Nuno Rodrigues ; Marie-Ludivine de Tauzia ; Lionel Colliandre ; Stéphane Bourg ; Pascal Bonnet ; Gérald Guillaumet ; Mohamed Akssira ; Anne Corlu ; Christiane Guillouzo ; Pauline Berthier ; Pascale Rio ; Marie-Lise Jourdan ; Hélène Bénédetti ; Sylvain Routier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：February 13, 2014
• 年：2014
• 卷：57
• 期：3
• 页码：613-631
• 全文大小：805K
• ISSN：1520-4804

文摘

The design, synthesis, and screening of dual PI3K/mTOR inhibitors that gave nanomolar enzymatic and cellular activities on both targets with an acceptable kinase selectivity profile are described. A docking study was performed to understand the binding mode of the compounds and to explain the differences in biological activity. In addition, cellular effects of the best dual inhibitors were determined on six cancer cell lines and compared to those on a healthy diploid cell line for cellular cytotoxicity. Two compounds are highly potent on cancer cells in the submicromolar range without any toxicity on healthy cells. A more detailed analysis of the cellular effect of these PI3K/mTOR dual inhibitors demonstrated that they induce G1-phase cell cycle arrest in breast cancer cells and trigger apoptosis. These compounds show an interesting kinase profile as dual PI3K/mTOR tool compounds or as a chemical series for further optimization to progress into in vivo experiments.