Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown.

摘要

聚（ADP-核糖）聚合酶-1（PARP-1）是碱基切除修复途径中的关键DNA修复酶，已被作为有吸引力的癌症治疗靶标进行研究。事实证明，对PARP-1的干预对携带BRCA1 / 2突变的癌细胞更为敏感。市场上已经有几种PARP-1抑制剂可用于治疗乳腺癌，卵巢癌和前列腺癌。很有可能，基于PARP-1的降解，新开发的针对嵌合体的蛋白水解（PROTAC）可能会提供更潜在的策略。在这里，我们报告基于PARP-1抑制剂olaparib和CRBN（大脑）配体来那度胺的组合，针对靶向Chimaera（PROTAC）的蛋白水解的设计，合成和评估。在SW620细胞中，我们的探针级降解剂化合物2有效诱导PARP-1降解，导致抗增殖，细胞凋亡，细胞周期停滞和癌细胞迁移抑制。因此，我们的发现为PARP-1敲除提供了一种新的化学探针。