Minimizing DNA trapping while maintaining activity inhibition via selective PARP1 degrader

作者：Li Chen, Yahui Zou, Renhong Sun, Mei Huang, Xiaotong Zhu, Xiao Tang, Xiaobao Yang, Dake Li, Gaofeng Fan, Yu Wang · 发表于：Cell Death and Disease · 年份：2024 · DOI：10.1038/s41419-024-07277-2 · 被引用次数：11 · 研究领域：PARP inhibition in cancer therapy、Protein Degradation and Inhibitors、Integrated Circuits and Semiconductor Failure Analysis

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.