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Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors

文献类型：期刊论文

作者Bi, Xiaoyang2,3; Chen, Yu3,4; Sun, Zhongya4,5; Lu, Wenchao1; Xu, Pan3,4; Lu, Tian4,6; Ding, Hong3,4; Zhang, Naixia7; Jiang, Hualiang3,4; Chen, Kaixian3,4,8
刊名BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
出版日期2020-11-15
卷号30期号:22页码:7
关键词Drug design CBP Bromodomain Inhibitor Acute myeloid leukemia
ISSN号0960-894X
DOI10.1016/j.bmcl.2020.127480
通讯作者Ding, Hong(hding@simm.ac.cn) ; Zhou, Bing(zhoubing@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn)
英文摘要CBP bromodomain could recognize acetylated lysine and function as transcription coactivator to regulate transcription and downstream gene expression. Furthermore, CBP has been shown to be related to many human malignancies including acute myeloid leukemia. Herein, we identified DC-CPin734 as a potent CBP bromodomain inhibitor with a TR-FRET IC50 value of 19.5 +/- 1.1 nM and over 400-fold of selectivity against BRD4 bromodomains through structure based rational drug design guided iterative chemical modification endeavoring to discover optimal tail-substituted tetrahydroquinolin derivatives. Moreover, DC-CPin734 showed potent inhibitory activity to AML cell line MV4-11 with an IC50 value of 0.55 +/- 0.04 mu M, and its cellular on-target effects were further evidenced by c-Myc downregulation results. In summary, DC-CPin734 showing good potency, selectivity and anti AML activity could serve as a potent and selective in vitro and in vivo probe of CBP bromodomain and a promising lead compound for future drug development.
WOS关键词C-MYC ; P300 ; COACTIVATOR ; ACETYLATION ; EXPRESSION ; GENE
资助项目National Key R&D Program of China[2017YFB0202600] ; National Key R&D Program of China[2018YFA0508200] ; National Natural Science Foundation of China[21820102008] ; National Natural Science Foundation of China[81973166] ; National Science and Technology Major Project[2018ZX09711002] ; K.C. Wong Education Foundation ; Science and Technology Commission of Shanghai Municipality[18431907100] ; Science and Technology Commission of Shanghai Municipality[Y811298033] ; Science and Technology Commission of Shanghai Municipality[19XD1404700] ; Personalized Medicines Molecular Signature-based Drug Discovery and Development (Strategic Priority Research Program of the Chinese Academy of Sciences)[XDA12020368]
WOS研究方向Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000594728300004
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/296240]  
专题新药研究国家重点实验室
通讯作者Ding, Hong; Zhou, Bing; Luo, Cheng
作者单位1.Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, 555 Zuchongshi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, 19 Yuquan Rd, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongshi Rd, Shanghai 201203, Peoples R China
5.Harbin Inst Technol, Sch Life & Technol, Harbin 150001, Peoples R China
6.Nanjing Univ Chinese Med, Jiangsu Key Lab High Technol Res TCM Formulae, 138 Xianlin Rd, Nanjing 210023, Peoples R China
7.Chinese Acad Sci, Dept Analyt Chem, Shanghai Inst Mat Med, 555 Zuchongshi Rd, Shanghai 201203, Peoples R China
8.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, 1 Wenhai Rd, Qingdao 266237, Peoples R China
推荐引用方式
GB/T 7714		 Bi, Xiaoyang,Chen, Yu,Sun, Zhongya,et al. Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2020,30(22):7.
APA Bi, Xiaoyang.,Chen, Yu.,Sun, Zhongya.,Lu, Wenchao.,Xu, Pan.,...&Luo, Cheng.(2020).Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,30(22),7.
MLA Bi, Xiaoyang,et al."Structure-based drug optimization and biological evaluation of tetrahydroquinolin derivatives as selective and potent CBP bromodomain inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 30.22(2020):7.

入库方式： OAI收割

来源：上海药物研究所

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