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.

中文翻译：

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使用选择性 PARP1 降解解偶联 PARP1 捕获和抑制。

已知 PARP1 抑制剂 (PARPi) 通过两种机制（PARP1 催化抑制和 PARP1 捕获）杀死肿瘤细胞。然而，这两种途径在介导 PARPi 的细胞毒性中的相对贡献尚不清楚。在这里，我们设计了一系列小分子 PARP 降解剂。用一种这样的化合物 iRucaparib-AP6 处理会导致高效且特异性的 PARP1 降解。iRucaparib-AP6 在体外阻断 PARP1 的酶活性，以及​​ PARP1 介导的完整细胞中的聚 ADP 核糖基化信号传导。这种策略模拟了 PARP1 基因缺失，这使得 PARP1 抑制与 PARP1 捕获的药理学解耦成为可能。最后，通过消耗 PARP1，iRucaparib-AP6 保护肌肉细胞和原代心肌细胞免受 DNA 损伤引起的能量危机和细胞死亡。总之，