Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction
文献类型：期刊论文
| 作者 | Lin, Zhitong3,4; Liu, Chen3,4; Yan, Ziqin3; Cheng, Jing2,3; Wang, Xiancheng2,3; Zhou, Feilong3; Lyu, Xilin3; Zhang, Shiyan2,3; Zhang, Daizhou1; Meng, Xiangjing1 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2024-04-15 |
| 卷号 | 270页码:16 |
| 关键词 | MDM2 p53 p21 Imidazolidinone Apoptosis |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2024.116366 |
| 通讯作者 | Meng, Xiangjing(fredamxj@163.com) ; Zhao, Yujun(yjzhao@simm.ac.cn) |
| 英文摘要 | Inhibition of MDM2/p53 interaction with small-molecule inhibitors stabilizes p53 from MDM2 mediated degradation, which is a promising strategy for the treatment of cancer. In this report, a novel series of 4-imidazolidinone - containing compounds have been synthesized and tested in MDM2/p53 and MDM4/p53 FP binding assays. Upon SAR studies, compounds 2 (TB114) and 22 were identified as the most potent inhibitors of MDM2/p53 but not MDM4/p53 interactions. Both 2 and 22 exhibited strong antiproliferative activities in HCT116 and MOLM-13 cell lines harboring wild type p53. Mechanistic studies show that 2 and 22 dose-dependently activated p53 and its target genes and induced apoptosis in cells based on the Western blot, qPCR, and flow cytometry assays. In addition, the antiproliferative activities of 2 and 22 were dependent on wild type p53, while they were not toxic to HEK-293 kidney cells. Furthermore, the on-target activities of 2 were general and applicable to other cancer cell lines with wild type p53. These attributes make 2 a good candidate for future optimization to discover a potential treatment of wild-type p53 cancer. |
| WOS关键词 | CLINICAL-TRIALS ; P53 PATHWAY ; DISCOVERY ; CANCER ; MDMX ; ANTAGONISTS ; ACTIVATION ; DESIGN |
| 资助项目 | National Natural Science Foundation of China[82273759] ; National Natural Science Foundation of China[82073682] ; Science and Technology Commission of Shanghai Municipality[22ZR1474500] ; Jinan Innovation Team Project[2021GXRC069] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001222410500001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311303]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Meng, Xiangjing; Zhao, Yujun |
| 作者单位 | 1.Shandong Acad Pharmaceut Sci, Shandong Prov Key Lab Biopharmaceut, Jinan 250101, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res & Small Mol Drug Res Ctr, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Lin, Zhitong,Liu, Chen,Yan, Ziqin,et al. Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,270:16. |
| APA | Lin, Zhitong.,Liu, Chen.,Yan, Ziqin.,Cheng, Jing.,Wang, Xiancheng.,...&Zhao, Yujun.(2024).Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,270,16. |
| MLA | Lin, Zhitong,et al."Synthesis and biological evaluation of 4-imidazolidinone-containing compounds as potent inhibitors of the MDM2/p53 interaction".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 270(2024):16. |
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。