Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines
文献类型：期刊论文
| 作者 | Liu, Ruiqi4,6; Yang, Hong5; Chen, Zonglong6; Zhou, Kaixin1,2,5; Shi, Qiongyu5; Li, Jiayi2,3; Huang, Yuting2,5; Huang, Xun2,3,5 ; Li, Yingxia6
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| 刊名 | BIOORGANIC CHEMISTRY
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| 出版日期 | 2022-07-01 |
| 卷号 | 124页码:15 |
| ISSN号 | 0045-2068 |
| 关键词 | Epigenetics p300 CBP Bromodomain inhibitors CCS1477 |
| DOI | 10.1016/j.bioorg.2022.105803 |
| 通讯作者 | Huang, Xun(xhuang@simm.ac.cn) ; Li, Yingxia(liyx417@fudan.edu.cn) |
| 英文摘要 | p300/CBP bromodomain plays an important role in transcriptional regulation, and its overexpression is closely related to various diseases such as cancers. Two inhibitors of this target are currently in clinical trials but only CCS1477 (A1) have been published with the chemical structure. Herein, we modified the structure of CCS1477 based on the principle of bioisosterism and reasonable scaffold hopping, and discovered a series of new p300 bromodomain inhibitors with improved potency. More tumor cell lines sensitive to p300/CBP bromodomain inhibition were also identified. Among our new inhibitors, (R)-5-methylpyrrolidin-2-one derivitive B4 was the most potent one which showed comparable inhibitory activity against p300 (IC50 = 0.060 mu M) as lead A1 (IC50 = 0.064 mu M) at molecular level, and performed more potent proliferation inhibitory activities on various tumor cells than A1. Further we found that compound B4 had the high cell permeability and overcame the defect of the high efflux rate of A1, which could also explain the possible reason why B4 showed more potent inhibitory activities on sensitive tumor cells than lead A1. Western blotting analysis proved the target effects that B4 could suppress the expression of c-Myc and reduce H3K27 acetylation significantly. Liver microsomal metabolic stability assay and hERG channel inhibition evaluation illustrate compound B4 is metabolic stabilizable in human liver microsomes and has no hERG risk, which further demonstrate the good drug-likeness of B4. Therefore, compound B4 is a promising compound for further optimization and development. |
| WOS关键词 | LYSINE ACETYLATION ; PROTEIN ; DISCOVERY ; LIGANDS ; REVEALS ; POTENT ; ACETYLTRANSFERASES |
| 资助项目 | National Natural Science Foundation of China[21922707] ; General Program of National Natural Science Foundation of China[82173835] ; Major projects of National Natural Science Foundation of China[81991523] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[2019CXJQ02] ; Open Program of State Key Laboratory of new Drug development[SIMM2105KF-04] ; SA-SIBS Scholarship Program ; Shanghai Municipal Science and Technology Major Project |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| WOS记录号 | WOS:000793725700005 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/300968]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Huang, Xun; Li, Yingxia |
| 作者单位 | 1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 4.Zhengzhou Univ, Sch Pharmaceut Sci, Zhengzhou 450001, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 6.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Liu, Ruiqi,Yang, Hong,Chen, Zonglong,et al. Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines[J]. BIOORGANIC CHEMISTRY,2022,124:15. |
| APA | Liu, Ruiqi.,Yang, Hong.,Chen, Zonglong.,Zhou, Kaixin.,Shi, Qiongyu.,...&Li, Yingxia.(2022).Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines.BIOORGANIC CHEMISTRY,124,15. |
| MLA | Liu, Ruiqi,et al."Design, synthesis and biological evaluation of (R)-5-methylpyrrolidin-2-ones as p300 bromodomain inhibitors with Anti-Tumor activities in multiple tumor lines".BIOORGANIC CHEMISTRY 124(2022):15. |
入库方式： OAI收割
来源：上海药物研究所
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