Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers
Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers
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发现 SK-575 作为一种高效、高效的 PARP1 蛋白水解靶向嵌合体降解剂，用于治疗癌症
DOI：
10.1021/acs.jmedchem.0c00821
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发表时间：
2020-10-08
影响因子：
7.3
通讯作者：
Chen, Yuanwei
中科院分区：
文献类型：
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作者：
Cao, Chaoguo;Yang, Jie;Chen, Yuanwei
核蛋白聚（ADP-核糖）聚合酶-1（PARP 1）在DNA的信号传导和修复中具有公认的作用，并且是癌症和其他人类疾病的经验证的治疗靶点。在这里，我们已经设计，合成，并评估了一系列的小分子PARP 1降解剂的蛋白水解靶向嵌合体（PROTAC）的概念的基础上。我们的努力已经导致发现了高效的PARP 1降解剂，如化合物18（SK-575）所示。SK-575有效抑制携带BRCA 1/2突变的癌细胞的生长，并诱导各种人类癌细胞中PARP 1的有效和特异性降解，即使在低皮摩尔浓度下。SK-575在作为单一药剂或与细胞毒性剂（例如替莫唑胺和顺铂）组合使用时在小鼠中实现持久的肿瘤生长抑制。这些数据表明SK-575是一种高效的PARP 1降解剂。
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.