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Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7

文献类型：期刊论文

作者Zhang, Hongjin7,8; Lin, Guohao6,7; Jia, Suyun4,5,7; Zhang, Ying3,7; Wu, Jianbo3,7; Tao, Yanxin1,2,5,7; Huang, Weixue4; Song, Meiru6,7; Ding, Ke4; Ma, Dawei4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-01-05
卷号263页码:21
ISSN号0223-5234
关键词Thieno[3 d ]pyrimidine derivative Cyclin-dependent kinase 7 Small molecule inhibitor Kinome selectivity Triple negative breast cancer
DOI10.1016/j.ejmech.2023.115955
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Targeting cyclin-dependent kinase 7 (CDK7) has emerged as a highly sought-after therapeutic strategy in oncology due to its duality of function in regulating biological processes, including cell cycle progression and transcriptional control. Herein, we describe the design, optimization and characterization of a series of thieno [3,2-d]pyrimidine derivatives as potent CDK7 inhibitors. The involvement of thiophene as core structure plays critical role in leading to the remarkable selectivity and incorporation of a fluorine atom into the piperidine ring enhances metabolic stability. Structure-activity relationship (SAR) study generated compound 36 as lead compound with potent inhibitory activity against CDK7 and good kinome selectivity in vitro. Compound 36 demonstrated strong efficacy against a triple negative breast cancer (TNBC) cell line-derived xenograft (CDX) mouse model upon oral administration at 5 mg/kg once daily. Therefore, it exhibits immense potential as a lead candidate for further exploration in the development of cancer therapy.
WOS关键词CDK7 ; CANCER ; INACTIVATION
资助项目Hangzhou Institute of Medicine (HIM) ; Zhejiang Cancer Hospital
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001127911600001
源URL[http://119.78.100.183/handle/2S10ELR8/308322]  
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.Tianjin Univ, Sch Life Sci, Tianjin 300072, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310014, Zhejiang, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai 20032, Peoples R China
5.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Mol Med, Hangzhou 310024, Zhejiang, Peoples R China
6.Zhejiang Canc Hosp, Hangzhou 310022, Zhejiang, Peoples R China
7.Chinese Acad Sci, Hangzhou Inst Med HIM, Hangzhou 310018, Zhejiang, Peoples R China
8.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. Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,263:21.
APA Zhang, Hongjin.,Lin, Guohao.,Jia, Suyun.,Zhang, Ying.,Wu, Jianbo.,...&Fan, Mengyang.(2024).Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,263,21.
MLA Zhang, Hongjin,et al."Discovery and optimization of thieno[3,2-d]pyrimidine derivatives as highly selective inhibitors of cyclin-dependent kinase 7".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 263(2024):21.

入库方式： OAI收割

来源：上海药物研究所

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