The recent advance and prospect of poly(ADP‐ribose) polymerase inhibitors for the treatment of cancer

聚ADP核糖聚合酶 聚合酶 DNA修复 合成致死 PARP抑制剂 表观遗传学 癌症 抗药性 同源重组 机制(生物学) 卵巢癌 癌症研究 生物 药理学 DNA 遗传学 基因 哲学 认识论
作者
Yi‐Ru Bai,Weiguang Yang,Rui Jia,Ju‐Shan Sun,Dan‐Dan Shen,Hong‐Min Liu,Shuo Yuan
出处
期刊:Medicinal Research Reviews [Wiley]
标识
DOI:10.1002/med.22069
摘要

Abstract 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.
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