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

  • Bioorg Med Chem Lett. 2022 May 1;63:128651. doi: 10.1016/j.bmcl.2022.128651.
Pei Chen  1 ,  Huachao Bin  2 ,  Yan Jiao  2 ,  Guifeng Lin  2 ,  Yun Zhang  3 ,  Anjie Xia  2 ,  Zhilin Pan  2 ,  Jingxin Qiao  2 ,  Yinping Guo  2 ,  Jingming Liu  2 ,  Yangli Zhou  2 ,  Linli Li  4
Affiliations
  • 1. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
  • 2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Macular Disease Research Laboratory, Department of Ophthalmology, West China Hospital, Sichuan University, Sichuan 610041, China.
  • 4. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China. Electronic address: [email protected].
PMID: 35245663 DOI: 10.1016/j.bmcl.2022.128651
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.

Keywords
ATR kinase; Ovarian cancer; Small molecule inhibitor; Structure–activity relationship.
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