Targeting polo-like kinase 1 to treat kidney diseases.

Globally, ∼850 million individuals suffer from some form of kidney disease. This staggering figure underscores the importance of continued research and innovation in the field of nephrology to develop effective treatments and improve overall global kidney health. In current research, the polo-like kinase (Plk) family has emerged as a group of highly conserved enzyme kinases vital for proper cell cycle regulation. Plks are defined by their N-terminal kinase domain and C-terminal polo-box domain, which regulate their catalytic activity, subcellular localization, and substrate recognition. Among the Plk family members, Plk1 has garnered significant attention due to its pivotal role in regulating multiple mitotic processes, particularly in the kidneys. It is a crucial serine-threonine (Ser-Thr) kinase involved in cell division and genomic stability. In this review, we delve into the types and functions of Plks, focusing on Plk1's significance in processes such as cell proliferation, spindle assembly, and DNA damage repair. The review also underscores Plk1's vital contributions to maintaining kidney homeostasis, elucidating its involvement in nuclear envelope breakdown, anaphase-promoting complex/cyclosome activation, and the regulation of mRNA translation machinery. Furthermore, the review discusses how Plk1 contributes to the development and progression of kidney diseases, emphasizing its overexpression in conditions such as acute kidney injury, chronic kidney disease, and so forth. It also highlights the importance of exploring Plk1 modulators as targeted therapies for kidney diseases in future. This review will help in understanding the role of Plk1 in kidney disease development, paving the way for the discovery and development of novel therapeutic approaches to manage kidney diseases effectively.

Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer.

In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC50 values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC50 = 17.3 nM, MDA-MB-361 IC50 = 8.4 nM, and MV4-11 IC50 = 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 µL·min-1·mg-1), acceptable pharmacokinetic profile (AUC0-t = 657 ng·h·mL-1, oral bioavailability of 21.4 %) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.

A novel L-shaped ortho-quinone analog as PLK1 inhibitor blocks prostate cancer cells in G2 phase.

Prostate cancer is the most common malignant tumor among men worldwide. Currently, the main treatments are radical prostatectomy, radiotherapy, chemotherapy, and endocrine therapy. However, most of them are poorly effective and induce side effects. Polo-like kinase 1 (PLK1) regulates cell cycle and mitosis. Its inhibitor BI2536 promotes the therapeutic effect of nilotinib in chronic myeloid leukemia, enhances the sensitivity of neural tube cell tumors to radiation therapy and PLK1 silencing enhances the sensitivity of squamous cell carcinoma to cisplatin. Therefore, the aim of this study was to evaluate the effect of the PLK1 inhibitor L-shaped ortho-quinone analog TE6 on prostate cancer. In vitro on prostate cancer cells showed that TE6 inhibited PLK1 protein expression and consequently cell proliferation by blocking the cell cycle at G2 phase. In vivo on a subcutaneous tumor model in nude mice confirmed that TE6 effectively inhibited tumor growth in nude mice, inhibited PLK1 expression and regulated the expression of cell cycle proteins such as p21, p53, CDK1, Cdc25C, and cyclinB1. Thus, PLK1 was identified as the target protein of TE6, these results reveal the critical role of PLK1 in the growth and survival of prostate cancer and point out the ability of TE6 on targeting PLK1, being a potential drug for prostate cancer therapy.