Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 19, Pages 11012-11033Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00821
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Funding
- National Natural Science Foundation of China [81672951]
- Chengdu Industrial Cluster Collaborative Innovation Project [2016-XT00-00024-GX]
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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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