PARP-1 is a crucial factor in repairing DNA single strand damage and maintaining genomic stability. However, the use of PARP-1 inhibitors is limited to combination with chemotherapy or radiotherapy, or as a single agent for indications carrying HRR defects. The ubiquitin-proteasome system processes the majority of cellular proteins and is the principal manner by which cells regulate protein homeostasis. Proteasome inhibitors can cooperate with PARP-1 inhibitors to inhibit DNA homologous recombination repair function. In this study, we designed and synthesized the first dual PARP-1 and proteasome inhibitor based on Olaparib and Ixazomib. Both compounds 42d and 42i exhibited excellent proliferation inhibition and dual-target synergistic effects on cells that were insensitive to PARP-1 inhibitors. Further mechanistic evaluations revealed that 42d and 42i could inhibit homologous recombination repair function by down-regulating the expression of BRCA1 and RAD51. Additionally, 42i induced more significant apoptosis and showed better inhibitory effect on cell proliferation in clonal formation experiments in breast cancer cells than 42d. In summary, our study presented a new class of dual PARP-1/proteasome inhibitors with significant synergistic effects for the treatment of breast cancer.

PARP-1是修复DNA单链损伤和维持基因组稳定性的关键因素。然而，PARP-1抑制剂的使用仅限于与化疗或放疗联合使用，或作为单一药物治疗HRR缺陷的适应症。泛素-蛋白酶体系统处理大多数细胞蛋白质，是细胞调节蛋白质稳态的主要方式。蛋白酶体抑制剂可以与PARP-1抑制剂配合抑制DNA同源重组修复功能。在本研究中，我们基于Olaparib和Ixazomib设计并合成了第一个PARP-1和蛋白酶体双重抑制剂。化合物42d和42i均对PARP-1抑制剂不敏感的细胞表现出优异的增殖抑制和双靶点协同作用。进一步的机制评估表明， 42d和42i可以通过下调BRCA1和RAD51的表达来抑制同源重组修复功能。此外，在乳腺癌细胞克隆形成实验中， 42i比42d诱导更显着的细胞凋亡，并显示出更好的细胞增殖抑制作用。总之，我们的研究提出了一类新的双 PARP-1/蛋白酶体抑制剂，对于治疗乳腺癌具有显着的协同作用。