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

Chunlan Pu1, Yu Tong2, Yuanyuan Liu3

  • 1State 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.

European Journal of Medicinal Chemistry
|April 17, 2022
PubMed

Insights

A novel PROTAC C8 effectively degrades PARP2 in wild-type triple-negative breast cancer (TNBC) cells. This targeted approach shows therapeutic potential for treating TNBC lacking BRCA mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Triple-negative breast cancer (TNBC) is aggressive and lacks effective targeted therapies.
  • PARP inhibitors are effective against BRCA-mutated TNBC but less so against wild-type TNBC.
  • Targeting DNA repair pathways offers a potential therapeutic strategy for TNBC.

Purpose of the Study:

  • To develop a novel therapeutic agent for wild-type TNBC.
  • To investigate the efficacy of a new PROTAC (C8) targeting PARP2.
  • To explore the role of DCAF16 E3 ligase in targeted protein degradation for TNBC treatment.

Main Methods:

  • Conjugation of a PARP1/2 inhibitor (Olaparib) with KB02 to create PROTAC C8.
  • Assessment of C8's ability to induce PARP2 degradation via DCAF16 E3 ligase recruitment.
  • In vitro and in vivo evaluation of C8's therapeutic potential in TNBC cell lines (MDA-MB-231).

Main Results:

  • PROTAC C8 demonstrated potent and specific degradation of PARP2.
  • C8 exhibited significant therapeutic potential in both in vitro and in vivo TNBC models.
  • The study confirmed DCAF16 E3 ligases as viable targets for PARP2 PROTAC design.

Conclusions:

  • C8 is a novel, PARP2-selective, DCAF16-based PROTAC with therapeutic promise.
  • This approach offers a potential treatment strategy for BRCA-wild-type TNBC.
  • DCAF16 E3 ligases are effective in designing PARP2-targeting PROTACs for cancer therapy.
Keywords:
DCAF16Degradation of PARP2MonotherapyPROTACsTriple-negative breast cancer

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