化学
PARP1
蛋白质水解
癌症研究
奥拉帕尼
合成致死
顺铂
DNA损伤
癌症
癌细胞
药理学
聚ADP核糖聚合酶
聚合酶
生物化学
DNA修复
DNA
酶
生物
化疗
遗传学
作者
Chaoguo Cao,Jie Yang,Yong Chen,Peiting Zhou,Yingwei Wang,Wu Du,Lifeng Zhao,Yuanwei Chen
标识
DOI:10.1021/acs.jmedchem.0c00821
摘要
The nuclear protein poly(ADP-ribose) polymerase-1 (PARP1) has a well-established role in the signaling and repair of DNA and is a validated therapeutic target for cancers and other human diseases. Here, we have designed, synthesized, and evaluated a series of small-molecule PARP1 degraders based on the proteolysis-targeting chimera (PROTAC) concept. Our efforts have led to the discovery of highly potent PARP1 degraders, as exemplified by compound 18 (SK-575). SK-575 potently inhibits the growth of cancer cells bearing BRCA1/2 mutations and induces potent and specific degradation of PARP1 in various human cancer cells even at low picomolar concentrations. SK-575 achieves durable tumor growth inhibition in mice when used as a single agent or in combination with cytotoxic agents, such as temozolomide and cisplatin. These data demonstrate that SK-575 is a highly potent and efficacious PARP1 degrader.
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