Discovery of 6,7-dihydro-5H-pyrrolo[3,4-d] pyrimidine derivatives as a new class of ATR inhibitors

[Display omitted] Ataxia telangiectasia and Rad3-related (ATR) kinase is a key regulating protein within the DNA damage response (DDR), responsible for sensing replication stress (RS), and has been considered as a potential target for cancer therapy. Herein, we report the discovery of a series of 6,...

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Published in:Bioorganic & medicinal chemistry letters 2022-05, Vol.63, p.128651-128651, Article 128651
Main Authors: Chen, Pei, Bin, Huachao, Jiao, Yan, Lin, Guifeng, Zhang, Yun, Xia, Anjie, Pan, Zhilin, Qiao, Jingxin, Guo, Yinping, Liu, Jingming, Zhou, Yangli, Li, Linli
Format: Article
Language:English
Subjects:
Ataxia Telangiectasia Mutated Proteins
ATR kinase
DNA Damage
Humans
Neoplasms - drug therapy
Ovarian cancer
Phosphorylation
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Small molecule inhibitor
Structure–activity relationship
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Summary:[Display omitted] Ataxia telangiectasia and Rad3-related (ATR) kinase is a key regulating protein within the DNA damage response (DDR), responsible for sensing replication stress (RS), and has been considered as a potential target for cancer therapy. Herein, we report the discovery of a series of 6,7-dihydro-5H-pyrrolo[3,4-d]-pyrimidine derivatives as a new class of ATR inhibitors. Among them, compound 5g exhibits an IC50 value of 0.007 μM against ATR kinase. In vitro, 5g displays good anti-tumor activity and could significantly reduce the phosphorylation level of ATR and its downstream signaling protein. Overall, this study provides a promising lead compound for subsequent drug discovery targeting ATR kinase.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2022.128651