High-throughput screening campaigns against a PI3K alpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds

doi:10.1038/s41401-018-0057-z

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 国家新药筛选中心

	High-throughput screening campaigns against a PI3K alpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds
	Wang, Jia2,7 ; Gong, Grace Qun 2,5,6,7; Zhou, Yan 2,7; Lee, Woo-Jeong 6; Buchanan, Christina Maree 5,6; Denny, William Alexander 4,5; Rewcastle, Gordon William 4,5; Kendall, Jackie Diane 4; Dickson, James Michael Jeremy 1,5; Flanagan, Jack Urquhart 4,5
刊名	ACTA PHARMACOLOGICA SINICA
	2018-11
卷号	39 期号:11 页码:1816-1822
关键词	high throughput screening PI3 kinase PI3K alpha H1047R inhibitors molecular modeling
ISSN号	1671-4083
DOI	10.1038/s41401-018-0057-z
文献子类	Article
英文摘要	The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3K alpha isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors.
资助项目	Ministry of Science and Technology of China[2014DFG32200] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Thousand Talents Program in China[00000000] ; New Zealand Health Research Council[HRC 13/1019]
WOS关键词	KINASE ALPHA INHIBITORS ; PHOSPHOINOSITIDE 3-KINASE ; PI3K PATHWAY ; PIK3CA GENE ; IN-VITRO ; DISCOVERY ; P110-ALPHA ; DOCKING ; GROWTH ; CANCER
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000448392900015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279519]
专题	国家新药筛选中心
通讯作者	Wang, Ming-Wei
作者单位	1.Univ Auckland, Sch Biol Sci, Auckland, New Zealand; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 4.Auckland Canc Soc Res Ctr, Auckland, New Zealand; 5.Maurice Wilkins Ctr, Auckland, New Zealand; 6.Univ Auckland, Dept Mol Med & Pathol, Auckland, New Zealand; 7.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Wang, Jia,Gong, Grace Qun,Zhou, Yan,et al. High-throughput screening campaigns against a PI3K alpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds[J]. ACTA PHARMACOLOGICA SINICA,2018,39(11):1816-1822.
APA	Wang, Jia.,Gong, Grace Qun.,Zhou, Yan.,Lee, Woo-Jeong.,Buchanan, Christina Maree.,...&Wang, Ming-Wei.(2018).High-throughput screening campaigns against a PI3K alpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds.ACTA PHARMACOLOGICA SINICA,39(11),1816-1822.
MLA	Wang, Jia,et al."High-throughput screening campaigns against a PI3K alpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds".ACTA PHARMACOLOGICA SINICA 39.11(2018):1816-1822.