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

Pei Chen; Huachao Bin; Yan Jiao; Guifeng Lin; Yun Zhang; Anjie Xia; Zhilin Pan; Jingxin Qiao; Yinping Guo; Jingming Liu; Yangli Zhou; Linli Li

doi:10.1016/j.bmcl.2022.128651

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. Epub 2022 Mar 1.

Authors

Pei Chen¹, Huachao Bin², Yan Jiao², Guifeng Lin², Yun Zhang³, Anjie Xia², Zhilin Pan², Jingxin Qiao², Yinping Guo², Jingming Liu², Yangli Zhou², Linli Li⁴

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: lilinli@scu.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins
DNA Damage
Humans
Neoplasms* / drug therapy
Phosphorylation
Protein Kinase Inhibitors* / pharmacology
Protein Kinase Inhibitors* / therapeutic use
Pyrimidines / pharmacology
Pyrimidines / therapeutic use

Substances

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