Discovery of novel 7,7-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidines as ATR inhibitors based on structure-based drug design

• Published in: European journal of medicinal chemistry Vol. 246; pp. 114945 - 114972
• Main Authors: Qi, Yinliang, Wang, Kun, Long, Bin, Yue, Hao, Wu, Yongshuo, Yang, Dexiao, Tong, Minghui, Shi, Xuan, Hou, Yunlei, Zhao, Yanfang
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.01.2023; Elsevier
• Subjects: Animals; Anticancer activity; Antineoplastic Agents - pharmacology; Apoptosis; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; ATR inhibitors; Cell Line, Tumor; Chemistry, Medicinal; Drug Design; Female; Fused pyrimidine derivatives; Humans; Life Sciences & Biomedicine; Ovarian Neoplasms; Pharmacology & Pharmacy; Protein Kinase Inhibitors - pharmacology; Pyrimidines - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Synthetic lethality; Synthetic lethality; ATR inhibitors; Fused pyrimidine derivatives; Anticancer activity; POTENT; AFFINITY; DNA-DAMAGE RESPONSE; KINASE; PLASMA-PROTEIN; BINDING; EFFICIENCY

ATR kinase is essential to the viability of replicating cells responding to the accumulation of single-strand breaks in DNA, which is an attractive anticancer drug target based on synthetic lethality. Herein we design, synthesize, and evaluate a novel series of fused pyrimidine derivatives as ATR in...