中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 药物化学研究室
Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors

文献类型：期刊论文

作者Lu, Wenchao1,2,4; Xiong, Huan1,3,6; Chen, Yu1,2,4; Wang, Chen1,2,4; Zhang, Hao2,4; Xu, Pan2,4; Han, Jie2,4; Xiao, Senhao2,9; Ding, Hong2; Chen, Zhifeng2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2018-11-01
卷号26期号:20页码:5397-5407
关键词Drug discovery Epigenetics Histone acetyltransferase P300/CBP
ISSN号0968-0896
DOI10.1016/j.bmc.2018.07.048
文献子类Article
英文摘要Histone acetyltransferases (HATs) relieve transcriptional repression by preferentially acetylation of epsilon-amino group of lysine residues on histones. Dysregulation of HATs is strongly correlated with etiology of several diseases especially cancer, thus highlighting the utmost significance of the development of small molecule inhibitors against this potential therapeutic target. In the present study, through virtual screening and iterative optimization, we identified DCH36_06 as a bona fide, potent p300/CBP inhibitor. DCH36_06 mediated p300/CBP inhibition leading to hypoacetylation on H3K18 in leukemic cells. The suppression of p300/ CBP activity retarded cell proliferation in several leukemic cell lines. In addition, DCH36_06 arrested cell cycle at G1 phase and induced apoptosis via activation of capase3, caspase9 and PARP that elucidated the molecular mechanism of its anti-proliferation activity. In transcriptome analysis, DCH36_06 altered downstream gene expression and apoptotic pathways-related genes verified by real-time PCR. Importantly, DCH36_06 blocked the leukemic xenograft growth in mice supporting its potential for in vivo use that underlies the therapeutic potential for p300/ CBP inhibitors in clinical translation. Taken together, our findings suggest that DCH36_06 may serve as a qualified chemical tool to decode the acetylome code and open up new opportunities for clinical intervention.
WOS关键词HISTONE ACETYLTRANSFERASE INHIBITOR ; DRUG DISCOVERY ; DNA-DAMAGE ; CELL-CYCLE ; CANCER ; ACETYLATION ; TRANSCRIPTION ; CURCUMIN ; PROLIFERATION ; REPRESSES
资助项目Ministry of Science and Technology of China[2015CB910304] ; National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81430084] ; National Natural Science Foundation of China[81803554] ; K. C. Wong Education Foundation[00000000] ; Chinese Academy of Sciences[XDA12020353] ; Chinese Academy of Sciences[XDA12050401]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000450747500003
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/279509]  
专题药物化学研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物发现与设计中心
通讯作者Zhang, Yuanyuan; Zhou, Bing; Luo, Cheng
作者单位1.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China;
4.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China;
5.Shanghai ChemPartner Co LTD, Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China;
6.Shanghai Univ, Coll Sci, Dept Chem, 99 Shangda Rd, Shanghai 200444, Peoples R China;
7.Guiyang Univ Tradit Chinese Med, Dept Pharm, South Dong Qing Rd, Guiyang 550025, Guizhou, Peoples R China;
8.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China;
9.ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China;
推荐引用方式
GB/T 7714		 Lu, Wenchao,Xiong, Huan,Chen, Yu,et al. Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2018,26(20):5397-5407.
APA Lu, Wenchao.,Xiong, Huan.,Chen, Yu.,Wang, Chen.,Zhang, Hao.,...&Luo, Cheng.(2018).Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,26(20),5397-5407.
MLA Lu, Wenchao,et al."Discovery and biological evaluation of thiobarbituric derivatives as potent p300/CBP inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 26.20(2018):5397-5407.

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。