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

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

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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