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Eur J Med Chem. 2016 Jan 27;108:644-654. doi: 10.1016/j.ejmech.2015.11.038. Epub 2015 Dec 2.

Discovery of 2-(2-aminopyrimidin-5-yl)-4-morpholino-N-(pyridin-3-yl)quinazolin-7-amines as novel PI3K/mTOR inhibitors and anticancer agents.

Author information

1
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
2
Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China.
3
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, PR China.
4
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address: lugui@mail.sysu.edu.cn.

Abstract

In this study, a series of novel 7 or 8-substituted 4-morpholine-quinazoline derivatives was designed and synthesized. Their PI3Kα inhibitory activities, antiproliferative activities against seven cancer cell lines, namely, PC-3, DU145, MCF-7, BT474, SK-BR-3, U937 and A431, were evaluated in vitro. Compound 17f proved to be a potential drug candidate with high PI3Kα inhibition activity (IC50 = 4.2 nM) and good antiproliferative activity. Compound 17f was also tested for its inhibitory activities against other kinases, such as PI3Kβ, PI3Kγ, PI3Kδ and mTOR, its effects on p-Akt (S473) and cell cycle. These results suggested that compound 17f could significantly inhibit the PI3K/Akt/mTOR pathway as a potent PI3K inhibitor and anticancer agent.

KEYWORDS:

4-Morpholine-quinazolines; Antiproliferative effects; Kinase inhibitor; Phosphoinositide 3-kinase (PI3K)

PMID:
26731167
DOI:
10.1016/j.ejmech.2015.11.038
[Indexed for MEDLINE]

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