2. Academic Validation
  3. Selective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer

Selective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer

  • Eur J Med Chem. 2022 Jun 5:236:114321. doi: 10.1016/j.ejmech.2022.114321.
Chunlan Pu 1,  Yu Tong 2,  Yuanyuan Liu 3,  Suke Lan 4,  Shirui Wang 3,  Guoyi Yan 5,  Hongjia Zhang 3,  Dan Luo 3,  Xinyu Ma 3,  Su Yu 3,  Qing Huang 3,  Rui Deng 3,  Rui Li 6
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; Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, Sichuan, 610031, China.
  • 2 West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children Sichuan University, Ministry of Education, Chengdu, Sichuan Province, China.
  • 3 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 4 College of Chemistry & Environment Protection Engineering, Southwest Minzu University, Chengdu, China.
  • 5 School of Pharmacy, Xinxiang University, Henan, 4453000, China.
  • 6 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: lirui@scu.edu.cn.
PMID: 35430559 DOI: 10.1016/j.ejmech.2022.114321
Abstract

Triple negative breast Cancer (TNBC) is a complex and heterogeneous neoplasm, and till now no effective therapies are available. PARP inhibitors, which target DNA repair, are lethal to those cells that have impaired homologous recombination (HR) pathway. So, PARP inhibitors might exert promising results in the treatment of BRCA-mutated TNBC, but show compromised effect to those wild-type TNBC. Herein, we describe a novel PROTACs C8, which was obtained by conjugating PARP1/2 inhibitor Olaparib to KB02, can induce potent and specific degradation of PARP2 by recruiting DCAF16 E3 Ligase for treatment of wild-type TNBC. Moreover, C8 exhibits therapeutic potential in TNBC cell lines MDA-MB-231 both in vitro and in vivo. These studies demonstrated that the DCAF16 E3 Ligases can be used in PARP2 PROTACs design, and C8, as a novel PARP2 selective DCAF16 based PROTACs, might be a promising lead compound for the treatment of BRCA-wild-type TNBC.

Keywords

DCAF16; Degradation of PARP2; Monotherapy; PROTACs; Triple-negative breast cancer.

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