Design, synthesis, and biological evaluation of some novel 4-aminoquinazolines as Pan-PI3K inhibitors

Bioorg Med Chem. 2019 Jul 1;27(13):2729-2740. doi: 10.1016/j.bmc.2019.04.024.

Huai-Wei Ding ¹, Shu Wang ², Xiao-Chun Qin ², Jian Wang ¹, Hong-Rui Song ¹, Qing-Chun Zhao ³, Shao-Jiang Song ⁴

Affiliations

1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
3 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: zhaoqingchun1967@163.com.
4 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: songsj99@163.com.

PMID: 31097403 DOI: 10.1016/j.bmc.2019.04.024

Abstract

A series of 4-aminoquinazolines derivatives containing hydrophilic group were designed and identified as potent Pan-PI3K inhibitors in this study. The results of antiproliferative assays in vitro showed that this series of compounds had strong inhibition of tumor growth, especially compound 7b for MCF-7 cells but weak inhibition to normal cells. PI3K kinase assay showed that 7b had high activity for three PI3K isoforms with the IC₅₀ values of picomole. The western blot assay indicated that 7b could decrease the phospho-Akt (S473) in a dose-dependent manner. Further experiments showed that 7b could induce Apoptosis in MCF-7 cells. Four key hydrogen bonding interactions were found in the docking of 7b with PI3K kinase. All these results suggested that 7b is a potent PI3K Inhibitor and could be considered as a potential candidate for the development of Anticancer agents.

Keywords

4-Aminoquinazolines; Anticancer; PI3K.

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