化学
细胞周期蛋白依赖激酶
选择性
细胞周期蛋白依赖激酶7
激酶
分子模型
立体化学
组合化学
生物化学
细胞周期
基因
细胞周期蛋白依赖激酶2
蛋白激酶A
催化作用
作者
Pengpeng Niu,Tao Yao,Guang Lin,Hao Xu,Qingyuan Meng,Kuo‐Chung Yang,Weixue Huang,Meiru Song,Ke Ding,Dawei Ma,Mengyang Fan
标识
DOI:10.1021/acs.jmedchem.3c01832
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.
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