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Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors

文献类型：期刊论文

作者Zhang, Hongjin8,9; Lin, Guohao7,8; Jia, Suyun5,6,8; Wu, Jianbo4,8; Zhang, Ying4,8; Tao, Yanxin2,3,6,8; Huang, Weixue5; Song, Meiru1,7,8; Ding, Ke5; Ma, Dawei5
刊名BIOORGANIC CHEMISTRY
出版日期2024-07-01
卷号148页码:15
关键词Cyclin-dependent kinase 7 Small molecular inhibitor Triple negative breast cancer Thieno[3,2-d]pyrimidine derivative
ISSN号0045-2068
DOI10.1016/j.bioorg.2024.107456
通讯作者Ding, Ke(dingk@sioc.ac.cn) ; Ma, Dawei(madw@sioc.ac.cn) ; Fan, Mengyang(sioc.mengyangfan@gmail.com)
英文摘要The targeting of cyclin-dependent kinase 7 (CDK7) has become a highly desirable therapeutic approach in the field of oncology due to its dual role in regulating essential biological processes, encompassing cell cycle progression and transcriptional control. We have previously identified a highly selective thieno[3,2-d]pyrimidine- based CDK7 inhibitor with demonstrated efficacy and safety in animal model. In this study, we sought to optimize the thieno[3,2-d]pyrimidine core to discover a novel series of CDK7 inhibitors with improved potency and pharmacokinetic (PK) properties. Through extensive structure-activity relationship (SAR) studies, compound 20 has emerged as the lead candidate due to its potent inhibitory activity against CDK7 and remarkable efficacy on MDA-MB-453 cells, a representative triple negative breast cancer (TNBC) cell line. Furthermore, 20 has demonstrated favorable oral bioavailability and exhibited highly desirable pharmacokinetic (PK) properties, making it a promising lead candidate for further structural optimization.
WOS关键词CTD KINASE ; CANCER ; INACTIVATION
资助项目Hangzhou Institute of Medicine (HIM) ; Zhejiang Cancer Hospital ; Center of Scientific Experiment, HIM ; Fundamental Research Funds of Henan Academy of Sciences, China[230618037]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:001291659400001
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/312794]  
专题中国科学院上海药物研究所
通讯作者Ding, Ke; Ma, Dawei; Fan, Mengyang
作者单位1.Henan Acad Sci, Inst Chem, Zhengzhou 450046, Henan, Peoples R China
2.Tianjin Univ, Sch Life Sci, Tianjin 300072, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
4.Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310014, Zhejiang, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 20032, Peoples R China
6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Mol Med, Hangzhou 310024, Zhejiang, Peoples R China
7.Zhejiang Canc Hosp, Hangzhou 310022, Zhejiang, Peoples R China
8.Chinese Acad Sci, Hangzhou Inst Med HIM, Hangzhou 310018, Zhejiang, Peoples R China
9.Tianjin Univ, Acad Med Engn & Translat Med AMT, Tianjin 300072, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Hongjin,Lin, Guohao,Jia, Suyun,et al. Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors[J]. BIOORGANIC CHEMISTRY,2024,148:15.
APA Zhang, Hongjin.,Lin, Guohao.,Jia, Suyun.,Wu, Jianbo.,Zhang, Ying.,...&Fan, Mengyang.(2024).Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors.BIOORGANIC CHEMISTRY,148,15.
MLA Zhang, Hongjin,et al."Design, synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel potent CDK7 inhibitors".BIOORGANIC CHEMISTRY 148(2024):15.

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来源：上海药物研究所

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