Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader

  • Cell Death Dis. 2024 Dec 18;15(12):898. doi: 10.1038/s41419-024-07277-2.
Li Chen  #  1 ,  Yahui Zou  #  1 ,  Renhong Sun  #  2 ,  Mei Huang  1 ,  Xiaotong Zhu  1 ,  Xiao Tang  1 ,  Xiaobao Yang  3 ,  Dake Li  4 ,  Gaofeng Fan  5  6 ,  Yu Wang  7  8
Affiliations
  • 1. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2. Gluetacs Therapeutics (Shanghai) Co, Ltd, Pudong District, Shanghai, China.
  • 3. Gluetacs Therapeutics (Shanghai) Co, Ltd, Pudong District, Shanghai, China. [email protected].
  • 4. Department of Gynecology, Nanjing Women and Children's Healthcare Hospital, Nanjing, China. [email protected].
  • 5. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. [email protected].
  • 6. Shanghai Clinical Research and Trial Center, Shanghai, China. [email protected].
  • 7. Department of Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
  • 8. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 39695097 DOI: 10.1038/s41419-024-07277-2
Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) catalyzes poly (ADP) ribosylation reaction, one of the essential post-translational modifications of proteins in eukaryotic cells. Given that PARP1 inhibition can lead to synthetic lethality in cells with compromised homologous recombination, this enzyme has been identified as a potent target for anti-cancer therapeutics. However, the clinical application of existing PARP1 inhibitors is restrained by side effects associated with DNA trapping and off-target effects, highlighting the need for improved therapeutic strategies. By integrating protein degradation technology, we synthesized a PROTAC molecule 180055 based on the Rucaparib junction and VHL ligand, which efficiently and selectively degraded PARP1 and inhibited PARP1 enzyme activity without a noticeable DNA trapping effect. Furthermore, 180055 kills tumor cells carrying BRCA mutations with a minor impact on the growth of normal cells both in vitro and in vivo. This suggests that 180055 is a PARP1-degrading compound with excellent pharmacological efficacy and extremely high biological safety that deserves further exploration and validation in clinical trials.

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