High-throughput screening campaigns against a PI3K alpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds
文献类型：期刊论文
| 作者 | Wang, Jia2,7 ; Gong, Grace Qun2,5,6,7; Zhou, Yan2,7; Lee, Woo-Jeong6; Buchanan, Christina Maree5,6; Denny, William Alexander4,5; Rewcastle, Gordon William4,5; Kendall, Jackie Diane4; Dickson, James Michael Jeremy1,5; Flanagan, Jack Urquhart4,5
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 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. |
| WOS关键词 | KINASE ALPHA INHIBITORS ; PHOSPHOINOSITIDE 3-KINASE ; PI3K PATHWAY ; PIK3CA GENE ; IN-VITRO ; DISCOVERY ; P110-ALPHA ; DOCKING ; GROWTH ; CANCER |
| 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研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000448392900015 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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