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Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors

文献类型：期刊论文

作者Niu, Pengpeng8,9; Tao, Yanxin2,4,6,8; Lin, Guohao7,8; Xu, Huiqi3,8; Meng, Qingyuan1,6,8; Yang, Kang3,8; Huang, Weixue5; Song, Meiru7,8; Ding, Ke5; Ma, Dawei5
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-04-08
页码20
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01832
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 duality of function (cell cycle regulation and gene transcription) of cyclin-dependent kinase 7 (CDK7) makes it an attractive oncology target and the discovery of CDK7 inhibitors has been a long-term pursuit by academia and pharmaceutical companies. However, achieving selective leading compounds is still difficult owing to the similarities among the ATP binding pocket. Herein, we detail the design and synthesis of a series of macrocyclic derivatives with pyrazolo[1,5-a]-1,3,5-triazine core structure as potent and selective CDK7 inhibitors. The diverse manners of macrocyclization led to distinguished selectivity profiles of the CDK family. Molecular dynamics (MD) simulation explained the binding difference between 15- and 16-membered macrocyclic compounds. Further optimization generated compound 37 exhibiting good CDK7 inhibitory activity and high selectivity over other CDKs. This work clearly demonstrated macrocyclization is a versatile method to finely tune the selectivity profile of small molecules and MD simulation can be a valuable tool in prioritizing designs of the macrocycle.
WOS关键词BASIS-SETS ; II CTD ; CDK7 ; PHOSPHORYLATION ; CANCER ; EXPLORATION ; CAK
资助项目Hangzhou Institute of Medical Sciences, Chinese Academy of Sciences ; Hangzhou Institute of Medicine (HIM) ; Zhejiang Cancer Hospital ; Scientific Experiment Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001200653200001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310747]  
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.Chinese Acad Sci, Inst Chem, Beijing 100190, Peoples R China
2.Tianjin Univ, Sch Life Sci, Tianjin 300072, Peoples R China
3.Zhejiang Univ Technol, Coll Pharmaceut Sci, Hangzhou 310014, Zhejiang, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Organ Chem, Shanghai, 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, 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		 Niu, Pengpeng,Tao, Yanxin,Lin, Guohao,et al. Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024:20.
APA Niu, Pengpeng.,Tao, Yanxin.,Lin, Guohao.,Xu, Huiqi.,Meng, Qingyuan.,...&Fan, Mengyang.(2024).Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,20.
MLA Niu, Pengpeng,et al."Design and Synthesis of Novel Macrocyclic Derivatives as Potent and Selective Cyclin-Dependent Kinase 7 Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY (2024):20.

入库方式： OAI收割

来源：上海药物研究所

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