SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3K delta) inhibitors
文献类型：期刊论文
| 作者 | Wei, Manman1,3; Zhang, Xi2; Wang, Xiang2; Song, Zilan1; Ding, Jian2 ; Meng, Ling-Hua2; Zhang, Ao1,3
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2017-01-05 |
| 卷号 | 125页码:1156-1171 |
| 关键词 | Chronic lymphocytic leukemia PI3K delta Structure-activity relationship 5-Alkynyl Quinazolinone |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2016.11.014 |
| 文献子类 | Article |
| 英文摘要 | PI3K delta is a key component in the aberrant signaling transduction in B cell malignancy, therefore specific targeting PI3K delta has become an attractive molecularly targeted therapy for chronic lymphocytic leukemia (CLL). Herein, we describe the discovery and optimization of a series of 5-alkynyl substituted PI3K delta inhibitors based on the first FDA-approved inhibitor idelalisib. Compound 8d bearing the 1-morpholinohex-5-yn-1-one moiety as the C5-substituent was identified to have high potency against PI3K delta (3.82 nM) and SU-DHL-6 cells (7.60 nM), respectively. It was 154-fold selective over PI3K alpha, 133-fold selective against PI3K beta, and 24-fold selective against PI3K gamma. Treatment of MOLT-4 and SU-DHL-6 cells with compound 8d for 1 h resulted in reduction of phosphorylation of both Akt (S473) and its downstream S6k1 (T389) in a concentration-dependent manner. Compound 8d showed potent anti proliferative activity as well against T lymphoblast MOLT-4, suggesting its potential activity in T-cell leukemia. (C) 2016 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | CHRONIC LYMPHOCYTIC-LEUKEMIA ; B-CELL ; ANTIGEN RECEPTOR ; P110 DELTA ; P110-DELTA ; THERAPY ; PATHWAY ; MECHANISMS ; LEUKOCYTES ; LYMPHOMA |
| 资助项目 | National Natural Science Foundation of China[81430080] ; National Natural Science Foundation of China[81503109] ; National Natural Science Foundation of China[81321092] ; Shanghai Commission of Science and Technology[14431905300] ; Shanghai Commission of Science and Technology[16XD1404600] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000390496600093 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275685]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物化学研究室 |
| 通讯作者 | Meng, Ling-Hua; Zhang, Ao |
| 作者单位 | 1.Chinese Acad Sci, SIMM, CAS Key Lab Receptor Res, Synthet Organ & Med Chem Lab, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, SIMM, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wei, Manman,Zhang, Xi,Wang, Xiang,et al. SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3K delta) inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2017,125:1156-1171. |
| APA | Wei, Manman.,Zhang, Xi.,Wang, Xiang.,Song, Zilan.,Ding, Jian.,...&Zhang, Ao.(2017).SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3K delta) inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,125,1156-1171. |
| MLA | Wei, Manman,et al."SAR study of 5-alkynyl substituted quinazolin-4(3H)-ones as phosphoinositide 3-kinase delta (PI3K delta) inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 125(2017):1156-1171. |
入库方式： OAI收割
来源：上海药物研究所
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