Discovery and SAR of Novel Disubstituted Quinazolines as Dual PI3Kalpha/mTOR Inhibitors Targeting Breast Cancer.

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 , and with single/double digit nanomolar IC values against both enzymes and acceptable aqueous solubility and stability to oxidative metabolism. One of those analogs, , possessed a sulfonamide substituent, which has not been described for this chemical scaffold before. The short direct synthetic routes, structure-activity relationship, 2D cell culture viability assays against normal fibroblasts and 3 breast cancer cell lines, and 3D culture viability assay against MCF7 cells for this series are described.