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

ABSTRACT: 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 IC₅₀ 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.

SUBMITTER: Al-Ashmawy AAK

PROVIDER: S-EPMC7667832 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Design, synthesis and structure-activity relationship (SAR) studies of 2,4-disubstituted pyrimidine derivatives: dual activity as cholinesterase and A?-aggregation inhibitors.

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