2. Academic Validation
  3. 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

  • J Med Chem. 2020 Oct 8;63(19):11012-11033. doi: 10.1021/acs.jmedchem.0c00821.
Chaoguo Cao 1,  Jie Yang 1,  Yong Chen 1,  Peiting Zhou 1,  Yingwei Wang 1,  Wu Du 2,  Lifeng Zhao 3,  Yuanwei Chen 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, China.
  • 2 Hinova Pharmaceuticals Inc., 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu 610041, China.
  • 3 Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
PMID: 32924477 DOI: 10.1021/acs.jmedchem.0c00821
Abstract

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.

Figures
Products