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Al-Ashmawy AAK , Elokely KM , Perez-Leal O , Rico M , Gordon J , Mateo G , Omar AM , Abou-Gharbia M , Childers WE Jr
Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer
ACS Med Chem Lett. 2020 Nov 12;11(11) :2156-2164
PMID: 33214824    PMCID: PMC7667832   
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The dual PI3Kα/ m TOR inhibitors represent a promising molecularly targeted therapy for cancer. Here, we documented the discovery of new 2,4-disubstituted quinazoline analogs as potent dual PI3Kα/sm TOR inhibitors. Our structure based chemistry endeavor yielded six excellent compounds 9e, 9f, 9g, 9k, 9m, and 9o with single/double digit nanomolar IC(50) values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, 9m, possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-activity relationship, in vitro 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and in vitro 3D culture viability assay against MCF7 cells for this series are described.
1948-5875 Al-Ashmawy, Aisha A K Elokely, Khaled M Perez-Leal, Oscar Rico, Mario Gordon, John Mateo, George Omar, Abdelsattar M Abou-Gharbia, Magid Childers, Wayne E Jr Journal Article ACS Med Chem Lett. 2020 Oct 12;11(11):2156-2164. doi: 10.1021/acsmedchemlett.0c00289. eCollection 2020 Nov 12.