设计、合成和生物评价pyrido[3,2-d]pyrimidine类化合物作为新型ATR抑制剂。
Design, synthesis, and biological evaluation of pyrido[3,2-d]pyrimidine derivatives as novel ATR inhibitors.
发表日期：2023 Apr 10
作者：
Yunxin Duan, Lili Zhuang, Yerong Xu, Haodong Cheng, Jiawei Xia, Tao Lu, Yadong Chen
来源：
BIOORGANIC CHEMISTRY
摘要：
以治疗具有特定DNA损伤应答缺陷的晚期实体肿瘤为目标，ATR激酶作为一种新的治疗策略正在追求中。在此，我们通过结构基础药物设计报道了一系列具有强效ATR抑制活性的吡啶并[3,2-d]嘧啶衍生物。其中，代表化合物10q在生物化学和细胞测定中对ATR表现出卓越的抑制活性。更重要的是，在不同物种的肝微粒体中，10q表现出良好的稳定性，同时与ATM抑制剂AZD1390联合处理对HT-29细胞也显示出适度的抑制活性。因此，该研究为进一步研究ATR的前沿化合物提供了有前途的线索。版权所有©2023 Elsevier Inc.
Targeting ataxia telangiectasia mutated and Rad3-related (ATR) kinase is being pursued as a new therapeutic strategy for the treatment of advanced solid tumor with specific DNA damage response deficiency. Herein, we report a series of pyrido[3,2-d]pyrimidine derivatives with potent ATR inhibitory activity through structure-based drug design. Among them, the representative compound 10q exhibited excellent potency against ATR in both biochemical and cellular assays. More importantly, 10q exhibited good liver microsomes stability in different species and also showed moderate inhibitory activity against HT-29 cells in combination treatment with the ATM inhibitor AZD1390. Thus, this work provides a promising lead compound against ATR for further study.Copyright © 2023 Elsevier Inc. All rights reserved.