ABSTRACT
The over-expression of Polo-like kinase-1 (PLK1) is associated with cancer prognosis due to its pivotal role in cell proliferation. The N-terminal catalytic domain (NCD) and C-terminal polo box domain (PBD) of PLK1 are critical for the activity of the protein. Drugs that inhibit PLK1 by targeting these domains are on clinical trials, but so far, none has been approved by FDA. Thus, this study targets the two domains of PLK1 to identify compounds with inhibitory potential. Four validated e-pharmacophore models from NCD (PDB ID: 2OU7 and 4J52) and PBD (PDB ID: 5NEI and 5NN2) were used to screen over 26,000 natural compounds from NPASS database. Hits were identified after the well-fitted compounds were subjected to molecular docking study and ADME prediction. The pIC50 and electronic behaviour of the identified hits selectively targeting NCD and PBD of PLK1 were predicted via an externally validated QSAR model and quantum mechanics. The results showed that CAA180504, CAA197326, CAA74619, CAA328856 modulating PLK1 at NCD, and CBB130581, CBB230713, CBB206123, CBB12656 and CBB267117 modulating PLK1 at PBD had better molecular docking scores, pharmacokinetics and drug-like properties than NCD (volasertib) and PBD (purpurogallin) reference inhibitors. The compounds all had satisfactory inhibitory (pIC50) values which range from 6.187 to 7.157. The electronic behaviours of understudied compounds using HOMO/LUMO and global descriptive parameters revealed the atomic portion of the compounds prone to donating and accepting electrons. In conclusion, the hit compounds identified from the library of natural compounds are worthy of further experimental validation.Communicated by Ramaswamy H. Sarma.
Subject(s)
Noncommunicable Diseases , Humans , Molecular Docking Simulation , Catalytic Domain , Cell Cycle Proteins , Protein Domains , Cell Proliferation , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/metabolismABSTRACT
Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.
Subject(s)
Neoplasms , Protein Kinase Inhibitors , Cell Cycle Proteins/genetics , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Polo-Like Kinase 1ABSTRACT
Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase implicated in spindle formation and cytokinesis in mammalian cells. Here, purified Plk1 was found to bind to reconstituted microtubules in vitro. Further, Plk1 was found to co-localize with interphase microtubules in MCF-7 cells and to co-immunoprecipitate with polymerized tubulin. The binding of Plk1 to interphase microtubules appeared to increase with an increase in the level of tubulin acetylation in MCF-7 cells. Interestingly, Plk1 inhibitor III, an inhibitor of Plk1 kinase activity, treatment increased the association of Plk1 with the interphase microtubules in MCF-7 cells. Therefore, the effect of inhibition of Plk1 kinase activity on the dynamic instability of microtubules was determined by time-lapse imaging in MCF-7 cells. Plk1 inhibitor III dampened the dynamic instability of microtubules. For example, Plk1 inhibitor III (3 µM) reduced the rate and extent of the growing phase by 28 and 48%, respectively, and inhibited the dynamicity of microtubules by 53% as compared to the microtubules in control MCF-7 cells. Plk1 inhibitor III treatment also increased the level of acetylated microtubules, indicating that it stabilizes microtubules. The findings indicated that Plk1 interacts with microtubules and Plk1 may have a role in the regulation of microtubule dynamics.
Subject(s)
Cell Cycle Proteins/metabolism , Microtubules/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/genetics , Female , Humans , MCF-7 Cells , Microtubules/genetics , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , Tubulin/genetics , Tubulin/metabolism , Polo-Like Kinase 1ABSTRACT
Polo-like kinase 1 (Plk1) is a promising target for cancer therapy due to its essential role in cell division. In addition to a highly conserved kinase domain, Plk1 also contains a Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. We adopted a fluorescence polarization assay and identified a new Plk1 PBD inhibitor T521 from a small-molecule compound library. T521 specifically inhibits the PBD of Plk1, but not those of Plk2-3. T521 exhibits covalent binding to some lysine residues of Plk1 PBD, which causes significant changes in the secondary structure of Plk1 PBD. Using a cell-based assay, we showed that T521 impedes the interaction between Plk1 and Bub1, a mitotic checkpoint protein. Moreover, HeLa cells treated with T521 exhibited dramatic mitotic defects. Importantly, T521 suppresses the growth of A549 cells in xenograft nude mice. Taken together, we have identified a novel Plk1 inhibitor that specifically disrupts the functions of Plk1 PBD and shows anticancer activity.
Subject(s)
Cell Cycle Proteins/antagonists & inhibitors , Drug Discovery , Protein Interaction Domains and Motifs/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Cycle Proteins/chemistry , Cell Proliferation/drug effects , Disease Models, Animal , Drug Screening Assays, Antitumor , Fluorescence Polarization/methods , HeLa Cells , High-Throughput Screening Assays , Humans , Kinetics , Mice , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Proto-Oncogene Proteins/chemistry , Xenograft Model Antitumor Assays , Polo-Like Kinase 1ABSTRACT
A new family of 3-aroylindolizines bearing a dimethoxytriazine unit in their position 1 was designed, synthesized and evaluated for their ability to inhibit tubulin polymerization and cellular growth in vitro. Compound 39 was the best candidate in the current study with a GI50 value of 870 nM on SNB-75 CNS cancer cells and of 920 nM on MDA-MB-231/ATCC breast cancer cells. The standard NCI Compare results indicated that indolizine 39 may target PLK1 (polo-like kinase 1).