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
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114945

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 inhibitors. As a result, compound 48f, with an IC50 value of 0.0030 μM against ATR, displayed strong monotherapy efficacy in ataxia-telangiectasia mutated (ATM) kinase-deficient tumor cells LoVo, SW620, OVCAR-3 cell lines with IC50 values of 0.040 μM, 0.095 μM, 0.098 μM, respectively. More importantly, the combination of 48f with AZD-1390, cisplatin, oxaliplatin, and olaparib respectively resulted in synergistic activity against HT-29, HCT116, A549, MCF-7, MDA-MB-231 cells. Moreover, 48f showed a favorable pharmacokinetic profile with a bioavailability of 30.0% in SD rats, acceptable PPB, high permeability (Papp A to B = 8.23 cm s−1 × 10−6), and low risk of drug-drug interactions. Collectively, compound 48f could be a promising compound for further investigation. [Display omitted] •Novel fused pyrimidine analogues were designed and synthesized for ATR inhibitors.•Compound 48f exhibited an IC50 value of 0.0030 μM against ATR, and excellent PK profile (F = 30%).•The combination treatment of 48f with AZD-1390, cisplatin, oxaliplatin, and olaparib resulted in synergistic activity.•The discovery of 48f provides a promising lead compound for the discovery of ATR inhibitors.