Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC, 29208, USA.
Eur J Med Chem. 2022 Jan 5;227:113926. doi: 10.1016/j.ejmech.2021.113926. Epub 2021 Oct 21.
Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase involved in cell cycle regulation and mitotic progression. Studies have shown that PLK1 is upregulated in many tumors and high levels are adversely related to a poor prognosis. Knocking down or inhibiting PLK1 results in synthetic lethality in PTEN deficient prostate tumors and Kras mutant colorectal tumors, further validating PLK1 as an oncotarget. Substrate recognition by PLK1 occurs through the Polo-Box Domain (PBD), which is a phospho-peptide binding site also responsible for subcellular localization. Much effort has been directed to target this kinase therapeutically through the ATP-binding site, and a few such inhibitors have advanced to clinical trials however with limited clinical efficacy. Moreover, it has been shown that a point mutation in PLK1 (C67V) confers dramatic cellular resistance to catalytic site inhibitors. An alternative approach to target PLK1 potently and selectively is through the PBD to block its protein-protein interactions. Through the REPLACE strategy, for converting peptide inhibitors into more drug-like non peptidic compounds, a PBD targeting compound series ("ABBAs"), has been identified and the key determinants of potency and selectivity elucidated through structure-activity relationship studies. In cellular experiments, the ABBAs were shown to lead to profound effects on the cell cycle, to inhibit tumor proliferation and overcome resistance of cells expressing the PLK1 C67V mutant to ATP-based inhibitors. These non-ATP competitive inhibitors of PLK1 were also used chemical biology probes to investigate the gene regulatory effects of PLK1, known to act on transcription factors such as p53.
丝氨酸/苏氨酸蛋白激酶 Polo 样激酶 1（PLK1）参与细胞周期调控和有丝分裂进程。研究表明，PLK1 在许多肿瘤中上调，高水平与预后不良相关。敲低或抑制 PLK1 会导致 PTEN 缺陷型前列腺肿瘤和 Kras 突变型结直肠肿瘤的合成致死，进一步验证了 PLK1 是一种癌基因靶点。PLK1 通过 Polo 盒结构域（PBD）识别底物，PBD 是一个磷酸肽结合位点，也负责亚细胞定位。人们已经投入大量精力通过 ATP 结合位点靶向这种激酶进行治疗，并且已经有一些这样的抑制剂进入临床试验，但临床疗效有限。此外，已经表明 PLK1 中的一个点突变（C67V）赋予了细胞对催化位点抑制剂的显著细胞抗性。一种替代方法是通过 PBD 来靶向 PLK1，从而阻断其蛋白-蛋白相互作用，从而有效地、选择性地靶向 PLK1。通过 REPLACE 策略，将肽抑制剂转化为更具类药性的非肽化合物，已经鉴定出一种针对 PBD 的化合物系列（“ABBAs”），并通过构效关系研究阐明了其效力和选择性的关键决定因素。在细胞实验中，这些 ABBAs 被证明对细胞周期有深远的影响，能够抑制肿瘤增殖，并克服表达 PLK1 C67V 突变体的细胞对基于 ATP 的抑制剂的耐药性。这些非 ATP 竞争性的 PLK1 抑制剂也被用作化学生物学探针，以研究 PLK1 的基因调控作用，PLK1 已知作用于转录因子，如 p53。
