Pharmacologic characterization of SHR8443, a novel dual inhibitor of phosphatidylinositol 3-kinase and mammalian target of rapamycin
文献类型：期刊论文
| 作者 | Xie, Chengying ; Chen, Xiangling; Zheng, Mingyue; Liu, Xiaohong; Wang, Hongbin; Lou, Liguang
|
| 刊名 | ONCOTARGET
 |
| 出版日期 | 2017-12-08 |
| 卷号 | 8期号:64页码:107977-107990 |
| 关键词 | BEZ235 drug resistance mTOR PI3K SHR8443 |
| ISSN号 | 1949-2553 |
| DOI | 10.18632/oncotarget.22439 |
| 文献子类 | Article |
| 英文摘要 | Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in human cancer and contributes to resistance to antitumor therapy. Inhibition of key signaling proteins in this pathway therefore represents an attractive targeting strategy for cancer therapy. Here, we show that SHR8443, an imidazo [4,5-c] quinoline derivative, inhibited mammalian target of rapamycin (mTOR) kinase and PI3K, especially PI3K alpha/delta/gamma isoforms with picomolar potency, by binding to the ATP subunits of the respective enzymes. Inhibition of PI3K/AKT/mTOR signaling by SHR8443 induced G(1) phase arrest, autophagy and apoptosis, and resulted in broad anti-proliferative activity against a panel of cancer cells with different genetic backgrounds. Furthermore, SHR8443 overcame resistance to RAF/MEK inhibitors and exhibited synergistic antitumor activity in combination with RAF/MEK inhibitors in vitro. Compared with the well-known PI3K/mTOR inhibitor BEZ235, SHR8443 showed broader and stronger efficacy against carcinoma xenografts, including those resistant to anti-HER2 antibody trastuzumab, in association with the inhibition of AKT and S6 phosphorylation in tumor tissues, and also caused no noticeable toxicity. Thus, our preclinical data show that SHR8443 is a dual PI3K/mTOR inhibitor with pharmaceutical properties favorable for use as an anticancer agent. |
| WOS关键词 | MUTANT BREAST-CANCER ; ANTITUMOR-ACTIVITY ; 3-KINASE/MAMMALIAN TARGET ; PI3K INHIBITORS ; PI3K/MTOR INHIBITOR ; POTENT INHIBITOR ; NVP-BEZ235 ; CELLS ; PATHWAY ; RESISTANCE |
| 资助项目 | National Natural Science Foundation of China[81273546] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09102008] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2013ZX09402102-001-004] |
| WOS研究方向 | Oncology ; Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000419564600049 |
| 出版者 | IMPACT JOURNALS LLC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272355]  |
| 专题 | 药理学第一研究室 |
| 通讯作者 | Lou, Liguang |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Chengying,Chen, Xiangling,Zheng, Mingyue,et al. Pharmacologic characterization of SHR8443, a novel dual inhibitor of phosphatidylinositol 3-kinase and mammalian target of rapamycin[J]. ONCOTARGET,2017,8(64):107977-107990. |
| APA | Xie, Chengying,Chen, Xiangling,Zheng, Mingyue,Liu, Xiaohong,Wang, Hongbin,&Lou, Liguang.(2017).Pharmacologic characterization of SHR8443, a novel dual inhibitor of phosphatidylinositol 3-kinase and mammalian target of rapamycin.ONCOTARGET,8(64),107977-107990. |
| MLA | Xie, Chengying,et al."Pharmacologic characterization of SHR8443, a novel dual inhibitor of phosphatidylinositol 3-kinase and mammalian target of rapamycin".ONCOTARGET 8.64(2017):107977-107990. |
入库方式： OAI收割
来源：上海药物研究所
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