Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist
文献类型：期刊论文
| 作者 | Xie, Chengying1 ; Zhao, Huajun2; Bao, Xubin1; Fu, Haoyu1; Lou, Liguang1
|
| 刊名 | JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
 |
| 出版日期 | 2018-11 |
| 卷号 | 22期号:11页码:5367-5377 |
| 关键词 | eltrombopag hetrombopag hollow-fibre assay thrombopoietin thrombopoietin receptor |
| ISSN号 | 1582-4934 |
| DOI | 10.1111/jcmm.13809 |
| 文献子类 | Article |
| 英文摘要 | Nonpeptide thrombopoietin receptor (TPOR/MPL) agonists, such as eltrombopag, have been used to treat thrombocytopenia of various aetiologies. Here, we investigated the pharmacological properties of hetrombopag, a new orally active small-molecule TPOR agonist, in preclinical models. Hetrombopag specifically stimulated proliferation and/or differentiation of human TPOR-expressing cells, including 32D-MPL and human hematopoietic stem cells, with low nanomolar EC50 values through stimulation of STAT, PI3K and ERK signalling pathways. Notably, hetrombopag effectively up-regulated G(1)-phase-related proteins, including p-RB, Cyclin D1 and CDK4/6, normalized progression of the cell cycle, and prevented apoptosis by modulating BCL-XL/BAK expression in 32D-MPL cells. Moreover, hetrombopag and TPO acted additively in stimulating TPOR-dependent signalling, promoting cell viability, and preventing apoptosis. Orally administered hetrombopag specifically promoted the viability and growth of 32D-MPL cells in hollow fibres implanted into nude mice with much higher potency than that of the well-known TPOR agonist, eltrombopag, in association with activation of TPOR-dependent signal transduction in vivo. Taken together, our findings indicate that, given its favourable pharmacological characteristics, hetrombopag may represent a new, orally active, small-molecule TPOR agonist for patients with thrombocytopenia. |
| WOS关键词 | IDIOPATHIC THROMBOCYTOPENIC PURPURA ; CHRONIC IMMUNE THROMBOCYTOPENIA ; HOLLOW-FIBER ASSAY ; PLATELET PRODUCTION ; GROWTH-FACTOR ; IN-VITRO ; ELTROMBOPAG ; MEGAKARYOCYTES ; MPL ; CHEMOTHERAPY |
| 资助项目 | Shanghai Science and Technology[18DZ2293200] ; National Natural Science Foundation of China[81273546] |
| WOS研究方向 | Cell Biology ; Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:000448279600018 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279520]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Lou, Liguang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China; 2.Zhejiang Chinese Med Univ, Coll Pharmaceut Sci, Hangzhou, Zhejiang, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Chengying,Zhao, Huajun,Bao, Xubin,et al. Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist[J]. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,2018,22(11):5367-5377. |
| APA | Xie, Chengying,Zhao, Huajun,Bao, Xubin,Fu, Haoyu,&Lou, Liguang.(2018).Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist.JOURNAL OF CELLULAR AND MOLECULAR MEDICINE,22(11),5367-5377. |
| MLA | Xie, Chengying,et al."Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist".JOURNAL OF CELLULAR AND MOLECULAR MEDICINE 22.11(2018):5367-5377. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。