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

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.