Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
文献类型：期刊论文
| 作者 | Zhang, Hefeng1,2; Peng, Xia3; Dai, Yang3; Shao, Jingwei1,2; Ji, Yinchun3; Sun, Yiming3; Liu, Bo3; Cheng, Xu2,3; Ai, Jing2,3 ; Duan, Wenhu1,2
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2021-04-08 |
| 卷号 | 64期号:7页码:3956-3975 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.0c02093 |
| 通讯作者 | Ai, Jing(jai@simm.ac.cn) ; Duan, Wenhu(whduan@simm.ac.cn) |
| 英文摘要 | The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment. |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[18431907100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002-011-016] ; Natural Science Foundation of China for Innovation Research Group[81821005] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2020CXJQ02] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000639043300025 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/296660]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ai, Jing; Duan, Wenhu |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Dept Med Chem, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Hefeng,Peng, Xia,Dai, Yang,et al. Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(7):3956-3975. |
| APA | Zhang, Hefeng.,Peng, Xia.,Dai, Yang.,Shao, Jingwei.,Ji, Yinchun.,...&Duan, Wenhu.(2021).Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor.JOURNAL OF MEDICINAL CHEMISTRY,64(7),3956-3975. |
| MLA | Zhang, Hefeng,et al."Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor".JOURNAL OF MEDICINAL CHEMISTRY 64.7(2021):3956-3975. |
入库方式： OAI收割
来源：上海药物研究所
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