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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 | 2020 Nov

REPOSITORIES: biostudies-literature

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

Al-Ashmawy Aisha A K AAK Elokely Khaled M KM Perez-Leal Oscar O Rico Mario M Gordon John J Mateo George G Omar Abdelsattar M AM Abou-Gharbia Magid M Childers Wayne E WE

ACS medicinal chemistry letters 20201012 11

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, ...[more]

PMID: 33214824

Dataset Information

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

Publications

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

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