Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
J Med Chem. 2022 Aug 11;65(15):10133-10160. doi: 10.1021/acs.jmedchem.2c00614. Epub 2022 Jul 25.
Polo-like kinase 1 (PLK1) plays an important role in a variety of cellular functions, including the regulation of mitosis, DNA replication, autophagy, and the epithelial-mesenchymal transition (EMT). PLK1 overexpression is often associated with cell proliferation and poor prognosis in cancer patients, making it a promising antitumor target. To date, at least 10 PLK1 inhibitors (PLK1i) have been entered into clinical trials, among which the typical kinase domain (KD) inhibitor BI 6727 (volasertib) was granted "breakthrough therapy designation" by the FDA in 2013. Unfortunately, many other KD inhibitors showed poor specificity, resulting in dose-limiting toxicity, which has greatly impeded their development. Researchers recently discovered many PLK1i with higher selectivity, stronger potency, and better absorption, distribution, metabolism, and elimination (ADME) characteristics. In this review, we emphasize the structure-activity relationships (SARs) of PLK1i, providing insights into new drugs targeting PLK1 for antitumor clinical practice.
丝氨酸/苏氨酸激酶 1（PLK1）在多种细胞功能中发挥重要作用，包括有丝分裂、DNA 复制、自噬和上皮-间充质转化（EMT）的调控。PLK1 过表达通常与癌症患者的细胞增殖和预后不良有关，使其成为有前途的抗肿瘤靶标。迄今为止，至少有 10 种 PLK1 抑制剂（PLK1i）已进入临床试验，其中典型的激酶结构域（KD）抑制剂 BI 6727（volasertib）于 2013 年被 FDA 授予“突破性治疗指定”。不幸的是，许多其他 KD 抑制剂特异性差，导致剂量限制毒性，这极大地阻碍了它们的发展。研究人员最近发现了许多具有更高选择性、更强效力和更好的吸收、分布、代谢和消除（ADME）特性的 PLK1i。在这篇综述中，我们强调了 PLK1i 的结构-活性关系（SARs），为抗肿瘤临床实践中针对 PLK1 的新药提供了见解。
