Design, synthesis, and biological evaluation of a new class of histone acetyltransferase p300 inhibitors
文献类型：期刊论文
| 作者 | Liu, Ruiqi1,3; Zhang, Zhuqing2,4; Yang, Hong2; Zhou, Kaixin2,4; Geng, Meiyu2,4 ; Zhou, Weicheng3; Zhang, Mingming1; Huang, Xun2,4; Li, Yingxia1
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2019-10-15 |
| 卷号 | 180页码:171-190 |
| 关键词 | p300 inhibitors Epigenetics Structure-activity relationship Sensitive tumor cell proliferation C646 |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2019.07.026 |
| 通讯作者 | Zhou, Weicheng(zhouweicheng58@163.com) ; Zhang, Mingming(zmmworld@gmail.com) ; Huang, Xun(xhuang@simm.ac.cn) ; Li, Yingxia(liyx417@fudan.edu.cn) |
| 英文摘要 | p300 is an important histone acetyltransferase in epigenetics, and its overexpression is closely related to various diseases such as cancers. C646 is one of the most representative p300 inhibitors and used in various studies of p300. However, its intrinsic drawbacks such as containing potentially toxic groups prevent it from further development. In order to find potent p300 inhibitors with good drug-like properties, C646 was chosen as the lead compound and a series of new p300 inhibitors were designed based on the principle of bioisosterism and reasonable scaffold hopping, and the structure-activity relationship was systematically explored. Ten of them were found to show comparable inhibitory activity as C646. The most potent compound, 1r (IC50 = 0.161 mu M), showed better p300 inhibitory activity than C646 with improved drug-like properties. Western blotting experiment confirmed that 1r could reduce the level of I-131(27 acetylation more significantly than C646. Further cellular assay indicated that it could inhibit the proliferation of human breast ductal carcinoma cell T47D and human breast cancer cell MCF7 with the IC50 values of 5.08 mu M and 22.54 mu M, respectively. Docking study of 1r with p300 protein showed the possible reasons for its higher inhibition activity. Thus, compound 1r might be with potential for development as a novel epigenetic agent targeting p300. (C) 2019 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | DISCOVERY ; CBP ; IDENTIFICATION ; TRANSCRIPTION ; ACETYLATION ; EXPRESSION ; REPRESSES ; RELEVANCE ; CBP/P300 ; PATHWAYS |
| 资助项目 | National Natural Science Foundation of China ; Collaborative Innovation Cluster project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000488307100015 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/282724]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhou, Weicheng; Zhang, Mingming; Huang, Xun; Li, Yingxia |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.China State Inst Pharmaceut Ind, Shanghai Inst Pharmaceut Ind, 285 Gebaini Rd, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Ruiqi,Zhang, Zhuqing,Yang, Hong,et al. Design, synthesis, and biological evaluation of a new class of histone acetyltransferase p300 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,180:171-190. |
| APA | Liu, Ruiqi.,Zhang, Zhuqing.,Yang, Hong.,Zhou, Kaixin.,Geng, Meiyu.,...&Li, Yingxia.(2019).Design, synthesis, and biological evaluation of a new class of histone acetyltransferase p300 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,180,171-190. |
| MLA | Liu, Ruiqi,et al."Design, synthesis, and biological evaluation of a new class of histone acetyltransferase p300 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 180(2019):171-190. |
入库方式： OAI收割
来源：上海药物研究所
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