Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the ataxia telangiectasia and RAD3-related (ATR) kinase
Design, synthesis, and biological characterization of proteolysis targeting chimera (PROTACs) for the ataxia telangiectasia and RAD3-related (ATR) kinase
复制标题
DOI：
10.1016/j.ejmech.2024.116167
复制
发表时间：
2024-02-02
影响因子：
6.7
通讯作者：
Sippl，Wolfgang
中科院分区：
文献类型：
--
作者：
Alfayomy，Abdallah M.;Ashry，Ramy;Sippl，Wolfgang
共济失调毛细血管扩张症和RAD3相关(ATR)激酶是DNA复制应激反应和DNA损伤检查点的关键调节因子。据报道，有几种有效和选择性的ATR抑制剂，其中四种目前正在与放射或化疗相结合的临床试验中。基于降解靶蛋白而不是抑制靶蛋白的思想，我们设计、合成了一个ATR靶向蛋白水解靶向嵌合体文库(PROTACs)，并对其进行了生物学表征。在所合成的化合物中，来那度胺为基础的PROTAC42I是最有前途的化合物。在胰腺癌细胞和宫颈癌细胞中，它将ATR水平降低到未经处理细胞的40%。42它通过蛋白酶体选择性地降解ATR，依赖于E3泛素连接酶组分Cereblon，而不影响相关的激酶ATM和DNA-PKcs。
The Ataxia telangiectasia and RAD3-related (ATR) kinase is a key regulator of DNA replication stress responses and DNA-damage checkpoints. Several potent and selective ATR inhibitors are reported and four of them are currently in clinical trials in combination with radio- or chemotherapy. Based on the idea of degrading target proteins rather than inhibiting them, we designed, synthesized and biologically characterized a library of ATR-targeted proteolysis targeting chimera (PROTACs). Among the synthesized compounds, the lenalidomide-based PROTAC42iwas the most promising. In pancreatic and cervix cancer cells cancer cells, it reduced ATR to 40 % of the levels in untreated cells.42iselectively degraded ATR through the proteasome, dependent on the E3 ubiquitin ligase component cereblon, and without affecting the associated kinases ATM and DNA-PKcs.42imay be a promising candidate for further optimization and biological characterization in various cancer cells.