Abstract：
The first examples of ataxia telangiectasia and Rad3-related (ATR) PROTACs were designed and synthesized. Among them, the most potent degrader, ZS-7, demonstrated selective and effective ATR degradation in ATM-deficient LoVo cells, with a DC50 value of 0.53 μM. Proteasome-mediated ATR degradation by ZS-7 lasted approximately 12 h after washout in the LoVo cell lines. Notably, ZS-7 demonstrated reasonable PK profiles and, as a single agent or in combination with cisplatin, showed improved antitumor activity and safety profiles compared with the parent inhibitor AZD6738 in a xenograft mouse model of LoVo human colorectal cancer cells upon intraperitoneal (i.p.) administration.
摘要：
设计并合成了共济失调毛细血管扩张症和Rad3相关（ATR）PROTACs的第一个实例。其中,最有效的降解剂，ZS-7在缺乏ATM的LoVo细胞中证明了选择性和有效的ATR降解，DC50值为0.53μM。在LoVo细胞系中洗脱后，ZS-7的蛋白酶体介导的ATR降解持续约12小时。值得注意的是,ZS-7展示了合理的PK剖面，作为单一药物或与顺铂联合使用，在腹膜内(i.p.)施用的LoVo人结直肠癌细胞的异种移植小鼠模型中,与亲本抑制剂AZD6738相比显示出改善的抗肿瘤活性和安全性概况。
