2. Academic Validation
  3. Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation

Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation

  • Nat Chem Biol. 2019 Dec;15(12):1223-1231. doi: 10.1038/s41589-019-0379-2.
Shuai Wang  # 1,  Lei Han  # 1,  Jungsoo Han 1,  Peng Li 1,  Qing Ding 1,  Qing-Jun Zhang 2,  Zhi-Ping Liu 2,  Chuo Chen 3,  Yonghao Yu 4
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA. Chuo.Chen@utsouthwestern.edu.
  • 4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA. Yonghao.Yu@utsouthwestern.edu.
  • # Contributed equally.
PMID: 31659317 DOI: 10.1038/s41589-019-0379-2
Abstract

PARP1 inhibitors (PARPi) are known to kill tumor cells via two mechanisms (PARP1 catalytic inhibition and PARP1 trapping). The relative contribution of these two pathways in mediating the cytotoxicity of PARPi, however, is not well understood. Here we designed a series of small molecule PARP degraders. Treatment with one such compound iRucaparib-AP6 results in highly efficient and specific PARP1 degradation. iRucaparib-AP6 blocks the enzymatic activity of PARP1 in vitro, and PARP1-mediated poly-ADP-ribosylation signaling in intact cells. This strategy mimics PARP1 genetic depletion, which enables the pharmacological decoupling of PARP1 inhibition from PARP1 trapping. Finally, by depleting PARP1, iRucaparib-AP6 protects muscle cells and primary cardiomyocytes from DNA-damage-induced energy crisis and cell death. In summary, these compounds represent 'non-trapping' PARP1 degraders that block both the catalytic activity and scaffolding effects of PARP1, providing an ideal approach for the amelioration of the various pathological conditions caused by PARP1 hyperactivation.

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