Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core
文献类型：期刊论文
| 作者 | Han, Mei1; Wang, Chengyan4; Ji, Yinchun2; Song, Zilan3; Xing, Li3; Su, Yi2; Wang, Xisheng4; Zhang, Ao3,5 ; Ai, Jing2,5; Geng, Meiyu2,5
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
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| 出版日期 | 2016-11-15 |
| 卷号 | 26期号:22页码:5399-5402 |
| 关键词 | EML4-ALK kinase Oxidative metabolism Benzo[b]carbazolone hERG Antitumor activity |
| ISSN号 | 0960-894X |
| DOI | 10.1016/j.bmcl.2016.10.039 |
| 文献子类 | Article |
| 英文摘要 | A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10 mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor. (C) 2016 Elsevier Ltd. All rights reserved. |
| WOS关键词 | ANAPLASTIC LYMPHOMA KINASE ; CRIZOTINIB RESISTANCE ; LUNG-CANCER ; ALECTINIB ; GENE ; ENTRECTINIB ; PF-06463922 ; DESIGN ; ROS1 |
| 资助项目 | Chinese National Science Foundation[81430080] ; Chinese National Science Foundation[81473243] ; Shanghai Commission of Science and Technology[16XD1404600] ; International Cooperative Program[GJHZ1622] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000388251400006 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275809]  |
| 专题 | 药物化学研究室 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 药理学第一研究室 |
| 通讯作者 | Zhang, Ao; Ai, Jing; Geng, Meiyu |
| 作者单位 | 1.Ocean Univ China, Sch Med & Pharm, Dept Pharmacol & Glycobiol, Qingdao 266003, Peoples R China; 2.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, SIMM, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 4.Univ Sci & Technol China, Nano Sci & Technol Inst, Suzhou 215123, Peoples R China; 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Han, Mei,Wang, Chengyan,Ji, Yinchun,et al. Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2016,26(22):5399-5402. |
| APA | Han, Mei.,Wang, Chengyan.,Ji, Yinchun.,Song, Zilan.,Xing, Li.,...&Geng, Meiyu.(2016).Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,26(22),5399-5402. |
| MLA | Han, Mei,et al."Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 26.22(2016):5399-5402. |
入库方式： OAI收割
来源：上海药物研究所
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