化疗常用于癌症治疗，但其应用仅限于特异性低、不良反应严重以及长期用药引起的耐药性等。聚（ADP-核糖）聚合酶（PARP）抑制剂是基于DNA损伤修复机制为解决这些棘手问题而开发的一类新型抗肿瘤药物，已广泛应用于卵巢癌、乳腺癌等癌症的治疗。通过诱导合成致死效应并捕获 BRCA 基因突变癌细胞中的 PARP-DNA 复合物来治疗癌症。近年来，PARP抑制剂已广泛与各种一线化疗药物、靶向药物和免疫检查点抑制剂联合应用，扩大了临床应用范围。然而，PARP抑制剂耐药性的复杂机制，包括同源重组的恢复、DNA复制叉的稳定、药物外排蛋白的过度表达和表观遗传修饰，对新型PARP抑制剂的开发提出了巨大的挑战和需要。在这篇综述中，我们将重点关注代表性 PARP 抑制剂的机制、构效关系和多药耐药性。此外，我们的目标是深入了解发展前景和新兴趋势，为临床应用提供指导，并为新型 PARP 抑制剂和降解剂的开发提供灵感。© 2024 Wiley periodicals LLC。

Chemotherapies are commonly used in cancer therapy, their applications are limited to low specificity, severe adverse reactions, and long-term medication-induced drug resistance. Poly(ADP-ribose) polymerase (PARP) inhibitors are a novel class of antitumor drugs developed to solve these intractable problems based on the mechanism of DNA damage repair, which have been widely applied in the treatment of ovarian cancer, breast cancer, and other cancers through inducing synthetic lethal effect and trapping PARP-DNA complex in BRCA gene mutated cancer cells. In recent years, PARP inhibitors have been widely used in combination with various first-line chemotherapy drugs, targeted drugs and immune checkpoint inhibitors to expand the scope of clinical application. However, the intricate mechanisms underlying the drug resistance to PARP inhibitors, including the restoration of homologous recombination, stabilization of DNA replication forks, overexpression of drug efflux protein, and epigenetic modifications pose great challenges and desirability in the development of novel PARP inhibitors. In this review, we will focus on the mechanism, structure-activity relationship, and multidrug resistance associated with the representative PARP inhibitors. Furthermore, we aim to provide insights into the development prospects and emerging trends to offer guidance for the clinical application and inspiration for the development of novel PARP inhibitors and degraders.© 2024 Wiley Periodicals LLC.