Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3K alpha H1047R mutant inhibitors

doi:10.1016/j.ejmech.2018.09.002

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	Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3K alpha H1047R mutant inhibitors
	Zhang, Ning 2; Yu, Zhimei 2; Yang, Xiaohong 2; Zhou, Yan 1,3; Wang, Jia1,3 ; Zhang, Shao-Lin 2; Wang, Ming-Wei1,3 ; He, Yun 2
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2018-10-05
卷号	158 页码:707-719
关键词	Anticancer drug Phosphatidylinositol 3-kinase Structure-activity relationship
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2018.09.002
文献子类	Article
英文摘要	Phosphatidylinositol 3-kinase alpha (PI3K alpha) is one of the most attractive therapeutic targets for cancer treatment. As our continuing endeavor to discover isoform and/or mutant selective class of PI3K inhibitors, herein we report the optimization of a structurally novel Pl3K alpha H1047R mutant inhibitor Hit-02 (EC50 = 115.3 mu M), which was identified from a high-throughput screening campaign. Structure-activity relationship analysis enabled us to discover compound 7h, which strongly inhibited PI3K alpha H1047R mutant with an EC50 value of 0.55 mu M, over 200-fold more potent than Hit-02, while having little effect on other PI3K isoforms. Western blotting assay suggested that 7h decreased the phosphorylation level of AKT, another proof that 7h inhibited PI3K alpha H1047R mutant function. Cell viability assay revealed that 7h inhibited HCT-116 cancer cell growth with an IC50 value of 10.9 mu M. In addition, 7h was found to arrest cell cycle at G2 phase but did not show any cell apoptosis effect. Furthermore, 7h obviously induced cell autophagy, which might contribute to its anti-proliferation effect in cancer cell. Collectively, all these data demonstrated that 7h could be a promising lead for the development of structurally novel PI3K alpha inhibitor. (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]
WOS关键词	BREAST-CANCER ; PIK3CA MUTATIONS ; PHOSPHOINOSITIDE 3-KINASES ; G1 ARREST ; PATHWAY ; AUTOPHAGY ; ZSTK474 ; CELLS ; GENE ; DERIVATIVES
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:000448094000044
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279539]
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, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shou Jing Rd, Shanghai 201203, Peoples R China; 2.Chongqing Univ, Chongqing Key Lab Nat Prod Synth & Drug Res, Sch Pharmaceut Sci, Chongqing 401331, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 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. Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3K alpha H1047R mutant inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,158:707-719.
APA	Zhang, Ning.,Yu, Zhimei.,Yang, Xiaohong.,Zhou, Yan.,Wang, Jia.,...&He, Yun.(2018).Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3K alpha H1047R mutant inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,158,707-719.
MLA	Zhang, Ning,et al."Synthesis, biological evaluation and structure-activity relationship of a novel class of PI3K alpha H1047R mutant inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 158(2018):707-719.