Center of Innovation in Personalized Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Republic of Korea.
Semin Cancer Biol. 2019 Jun;56:47-55. doi: 10.1016/j.semcancer.2017.11.004. Epub 2017 Nov 6.
Cancer is a disease that has been the focus of scientific research and discovery and continues to remain so. Polo-like kinases (PLKs) are basically serine/threonine kinase enzymes that control cell cycle from yeast to humans. PLK-1 stands for 'Polo-like kinase-1'. It is the most investigated protein among PLKs. It is crucial for intracellular processes, hence a 'hot' anticancer drug-target. Accelerating innovations in Enzoinformatics and associated molecular visualization tools have made it possible to literally perform a 'molecular level walk' traversing through and observing the minutest contours of the active site of relevant enzymes. PLK-1 as a protein consists of a kinase domain at the protein N-terminal and a Polo Box Domain (PBD) at the C-terminal connected by a short inter-domain linking region. PBD has two Polo-Boxes. PBD of PLK-1 gives the impression of "a small clamp sandwiched between two clips", where the two Polo Boxes are the 'clips' and the 'phosphopeptide' is the small 'clamp'. Broadly, two major sites of PLK-1 can be potential targets: one is the adenosine-5'-triphosphate (ATP)-binding site in the kinase domain and the other is PBD (more preferred due to specificity). Targeting PLK-1 RNA and the interaction of PLK-1 with a key binding partner can also be approached. However, the list of potent small molecule inhibitors targeting the PBD site of PLK-1 is still not long enough and needs due input from the scientific community. Recently, eminent scientists have proposed targeting the 'Y'-shaped pocket of PLK-1-PBD and encouraged design of ligands that should be able to concurrently bind to two or more modules of the 'Y' pocket. Hence, it is suggested that during molecular interaction analyses, particular focus should be kept on the moiety in each ligand/drug candidate which directly interacts with the amino acid residue(s) that belong(s) to one of the three binding modules which together create this Y-shaped cavity. This obviously includes (but it is not limited to) the 'shallow cleft'-forming residues i.e. Trp414, H538 and K540, as significance of these binding residues has been consistently highlighted by many studies. The present article attempts to give a concise yet critically updated overview of targeting PLK-1 for cancer therapy.
癌症是一个一直以来都是科学研究和发现的焦点的疾病。 Polo 样激酶（PLKs）基本上是一种从酵母到人类控制细胞周期的丝氨酸/苏氨酸激酶酶。PLK-1 代表“Polo 样激酶-1”。它是 PLKs 中研究最多的蛋白质。它对于细胞内过程至关重要，因此是一种“热门”的抗癌药物靶点。Enzoinformatics 和相关分子可视化工具的创新加速，使得人们可以在相关酶的活性位点上进行“分子水平行走”，观察到最微小的轮廓。PLK-1 作为一种蛋白质，由蛋白 N 端的激酶结构域和 C 端的 Polo 盒结构域（PBD）组成，两者由短的结构域连接区连接。PBD 有两个 Polo 盒。PLK-1 的 PBD 给人留下了“一个小夹子夹在两个夹子之间”的印象，其中两个 Polo 盒是“夹子”，而“磷酸肽”是小“夹子”。广义上，PLK-1 有两个主要的潜在靶点：一个是激酶结构域中的腺苷-5'-三磷酸（ATP）结合位点，另一个是 PBD（由于特异性，更受欢迎）。还可以靶向 PLK-1 RNA 及其与关键结合伙伴的相互作用。然而，针对 PLK-1 PBD 位点的有效小分子抑制剂的清单还不够长，需要科学界的投入。最近，杰出的科学家们提出了靶向 PLK-1-PBD 的“Y”形口袋的目标，并鼓励设计能够同时结合“Y”口袋两个或更多模块的配体。因此，建议在分子相互作用分析中，特别关注每个配体/药物候选物中与属于三个结合模块之一的氨基酸残基直接相互作用的部分，这三个结合模块共同形成这个 Y 形腔。这显然包括（但不限于）形成“浅裂缝”的残基，即 Trp414、H538 和 K540，因为许多研究一直强调这些结合残基的重要性。本文试图简要但批判性地综述了针对癌症治疗的 PLK-1 靶向治疗。
