American Chemical Society
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Discovery of SK-575 as a Highly Potent and Efficacious Proteolysis-Targeting Chimera Degrader of PARP1 for Treating Cancers

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posted on 2020-09-24, 13:34 authored by Chaoguo Cao, Jie Yang, Yong Chen, Peiting Zhou, Yingwei Wang, Wu Du, Lifeng Zhao, Yuanwei Chen
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.