Design, synthesis and bioactivity evaluation of a series of quinazolinone derivatives as potent PI3Kγ antagonist

被引：1
|
作者：
Liang, Yuqing [1 ]
Zheng, Yanjun [1 ]
Yang, Junjie [1 ]
Ke, Jiahua [1 ]
Cheng, Kui [1 ]
机构：
[1] Southern Med Univ, Sch Pharmaceut Sci, Guangdong Prov Key Lab New Drug Screening, Guangzhou Key Lab Drug Res Emerging Virus Prevent, Guangzhou 510515, Peoples R China
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2023年 / 84卷
基金：
中国国家自然科学基金;
关键词：
Phosphatidylinositol 3-kinase gamma (PI3K gamma); Structure-activity relationship; Small molecule; Anti-cancer; PI3K PATHWAY; INFLAMMATION; INHIBITION; BINDING; CANCER;
D O I：
10.1016/j.bmc.2023.117261
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Targeting PI3K gamma would be a useful strategy for treating inflammatory and cancer diseases. However, the development of selective inhibitors of PI3K gamma is very challenging due to the high structural and sequence homology with other PI3K isoforms. A series of quinazolinone derivatives were designed, synthesized and biologically evaluated as PI3K gamma-selective inhibitors. Among all the 28 compounds, compound 9b was found to be the most potent selective inhibitor with IC50 values of 13.11 nM against PI3K gamma kinase. Additionally, compound 9b could generate toxicity on leukemia cells in a panel of 12 different of cancer cell lines with the IC50 value of 2.41 +/- 0.11 mu M on Jurkat cell. Preliminary mechanism studies indicated that compound 9b through inhibit the activity of PI3K-AKT in human and murine leukemia cells, and activated phosphorylated p38 and phosphorylated ERK presented potent antiproliferative activity, which provided a potent small molecule for further cancer therapy.
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页数：16
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