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

Abstract

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.

• Authors: Pei Chen, Huachao Bin, Yan Jiao, Guifeng Lin, Yun Zhang, Anjie Xia, Zhilin Pan, Jingxin Qiao, Yinping Guo, Jingming Liu, Yangli Zhou, Linli Li
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 63 Pg. 128651 (05 01 2022) ISSN: 1464-3405 [Electronic] England
• PMID: 35245663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Ataxia Telangiectasia Mutated Proteins
• DNA Damage
• Humans
• Neoplasms (drug therapy)
• Phosphorylation
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)