Design, synthesis, and biological activity of pyridopyrimidine scaffolds as novel PI3K/mTOR dual inhibitors

Journal of Medicinal Chemistry
Thibault SauratSylvain Routier

Abstract

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.

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Citations

Dec 3, 2014·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jean-Yves MérourSylvain Routier
May 27, 2015·Biochimica Et Biophysica Acta·Tomasz RzymskiKrzysztof Brzózka
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Mar 22, 2015·European Journal of Medicinal Chemistry·F BuronS Routier
Sep 27, 2018·Medicinal Research Reviews·Mohammed S Abdel-MaksoudChang-Hyun Oh
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Nov 21, 2020·ACS Medicinal Chemistry Letters·Aisha A K Al-AshmawyWayne E Childers
Dec 17, 2016·The Journal of Organic Chemistry·Anthony ChampiréSylvain Routier
Nov 15, 2017·Organic Letters·Thomas A ClohessyAllan J B Watson
Feb 6, 2018·Journal of Medicinal Chemistry·Nicholas A Meanwell
Dec 26, 2018·Journal of Medicinal Chemistry·Aimie E Garces, Michael J Stocks

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