Difuran-substituted quinoxalines as a novel class of PI3K alpha H1047R mutant inhibitors: Synthesis, biological evaluation and structure activity relationship

doi:10.1016/j.ejmech.2018.07.061

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	Difuran-substituted quinoxalines as a novel class of PI3K alpha H1047R mutant inhibitors: Synthesis, biological evaluation and structure activity relationship
	Zhang, Ning 2; Yu, Zhimei 2; Yang, Xiaohong 2; Zhou, Yan 1,3; Tang, Qing 2; Hu, Ping 2; Wang, Jia1,3 ; Zhang, Shao-Lin 2; Wang, Ming-Wei1,3 ; He, Yun 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-09-05
卷号	157 页码:37-49
关键词	Proliferation Anticancer drug Phosphatidylinositol 3-kinase inhibitor Apoptosis Structure-activity relationship
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.07.061
文献子类	Article
英文摘要	Phosphatidylinositol 3-kinase alpha (PI3K alpha) is the most frequently mutated kinase in human cancers, making it an attractive therapeutic target for cancer treatment. We identified a structurally novel PI3K alpha H1047R mutant inhibitor Hit-01 (EC50 = 76.0 mu M) through a high-throughput screening campaign. Chemical optimizations enabled us to discover compound 7b, which strongly inhibited PI3K alpha H1047R mutant with an EC50 value of 0.137 mu M, over 500-fold more potent than Hit-01. Western blotting analysis suggested that 7b could decrease the phosphorylation level of p-AKT, another proof that 7b inhibited PI3K alpha H1047R function. Cell viability assay revealed that 7b inhibited HCT116 cancer cell growth with an IC50 value of 11.23 mu M. In addition, 7b was found to arrest cell cycle at G1 phase and induce cell apoptosis via up regulation of caspase-3, caspase-8 and caspase-9 protein expressions. Collectively, all these data demonstrated that 7b could be a promising lead for the development of structurally novel PI3K alpha inhibitors. (C) 2018 Elsevier Masson SAS. All rights reserved.
资助项目	National Natural Science Foundation of China[21572027] ; Ministry of Science and Technology of China[2014DFG32200] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Thousand Talents Program in China[00000000]
WOS关键词	METASTATIC BREAST-CANCER ; PI3K/AKT/MTOR SIGNALING PATHWAY ; ADVANCED SOLID TUMORS ; ONE-POT SYNTHESIS ; I PI3K INHIBITOR ; PIK3CA MUTATIONS ; PHOSPHOINOSITIDE 3-KINASE ; PHASE-I ; COLORECTAL-CANCER ; CLINICAL-TRIALS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000447480000004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279587]
专题	国家新药筛选中心
通讯作者	Zhang, Shao-Lin; Wang, Ming-Wei; He, Yun
作者单位	1.Chinese Acad Sci, Key Lab Receptor Res, Shanghai Inst Mat Med, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China 2.Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China; 3.Chinese Acad Sci, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Ning,Yu, Zhimei,Yang, Xiaohong,et al. Difuran-substituted quinoxalines as a novel class of PI3K alpha H1047R mutant inhibitors: Synthesis, biological evaluation and structure activity relationship[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,157:37-49.
APA	Zhang, Ning.,Yu, Zhimei.,Yang, Xiaohong.,Zhou, Yan.,Tang, Qing.,...&He, Yun.(2018).Difuran-substituted quinoxalines as a novel class of PI3K alpha H1047R mutant inhibitors: Synthesis, biological evaluation and structure activity relationship.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,157,37-49.
MLA	Zhang, Ning,et al."Difuran-substituted quinoxalines as a novel class of PI3K alpha H1047R mutant inhibitors: Synthesis, biological evaluation and structure activity relationship".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 157(2018):37-49.