66 results match your criteria plk1 selectivity


Design and Synthesis of a Novel PLK1 Inhibitor Scaffold Using a Hybridized 3D-QSAR Model.

Int J Mol Sci 2021 Apr 8;22(8). Epub 2021 Apr 8.

College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Korea.

Polo-like kinase 1 (PLK1) plays an important role in cell cycle progression and proliferation in cancer cells. PLK1 also contributes to anticancer drug resistance and is a valuable target in anticancer therapeutics. To identify additional effective PLK1 inhibitors, we performed QSAR studies of two series of known PLK1 inhibitors and proposed a new structure based on a hybridized 3D-QSAR model. Read More

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[Mining Polo-Box domain of Polo-like kinase 1 as a new therapeutic target for cancer].

Sheng Wu Gong Cheng Xue Bao 2020 Nov;36(11):2298-2312

Institute for Drug Screening and Evaluation, Wannan Medical College, Wuhu 241002, Anhui, China.

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. Read More

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November 2020

Discovery of methyl 3-((2-((1-(dimethylglycyl)-5-methoxyindolin-6-yl)amino)-5-(trifluoro-methyl) pyrimidin-4-yl)amino)thiophene-2-carboxylate as a potent and selective polo-like kinase 1 (PLK1) inhibitor for combating hepatocellular carcinoma.

Eur J Med Chem 2020 Nov 8;206:112697. Epub 2020 Aug 8.

State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; State-province Joint Engineering Laboratory of Targeted Drugs from Natural Products, Xiamen University, Xiamen, Fujian, 361102, China. Electronic address:

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide and targeted therapeutics exhibit limited success. Polo-like kinase 1 (PLK1), a Ser/Thr kinase, plays a pivotal role in cell-cycle regulation and is considered a promising target in HCC. Here, via structural optimization using both biochemical kinase assays and cellular antiproliferation assays, we discovered a potent and selective PLK1 kinase inhibitor, compound 31. Read More

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November 2020

Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide-Protein Interactions.

Molecules 2020 Jun 18;25(12). Epub 2020 Jun 18.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.

Protein-protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by taking advantage of the fact that large interacting surfaces are often characterized by confined "hot spot" regions, where interactions contribute disproportionately to overall binding energies. Peptides afford valuable starting points for developing PPI inhibitors because of their high degrees of functional diversity and conformational adaptability. Read More

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Antiviral activity of PLK1-targeting siRNA delivered by lipid nanoparticles in HBV-infected hepatocytes.

Antivir Ther 2020 ;25(3):151-162

Cancer Research Center of Lyon (CRCL), INSERM U1052, Lyon, France.

Background: A link between HBV and PLK1 was clearly evidenced in HBV-driven carcinogenesis, and we have also recently shown that PLK1 is a proviral factor in the early phases of HBV infection. Moreover, we have shown that BI-2536, a small molecule PLK1 inhibitor, was very efficient at inhibiting HBV DNA neosynthesis, notably by affecting nucleocapsid assembly as a result of the modulation of HBc phosphorylation. Yet, as small molecule kinase inhibitors often feature poor selectivity, a more specific and safer strategy to target PLK1 would be needed for a potential development against chronic HBV infections. Read More

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January 2020

Peptidomimetic Polo-Box-Targeted Inhibitors that Engage PLK1 in Tumor Cells and Are Selective against the PLK3 Tumor Suppressor.

ChemMedChem 2020 06 28;15(12):1058-1066. Epub 2020 Apr 28.

Drug Discovery and Biomedical Sciences College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.

The polo-box domain (PBD) of PLK1 determines mitotic substrate recognition and subcellular localization. Compounds that target PLK1 selectively are required due to the tumor-suppressor roles of PLK3. A structure-activity analysis of the PBD phosphopeptide binding motif has identified potent peptides that delineate the determinants required for mimicry by nonpeptidic inhibitors and provide insights into the structural basis for the selectivity of inhibitors for the PLK1 PBD. Read More

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A Genetic Toggle for Chemical Control of Individual Plk1 Substrates.

Cell Chem Biol 2020 03 3;27(3):350-362.e8. Epub 2020 Feb 3.

Department of Medicine, Division of Hematology/Oncology, University of Wisconsin, 1111 Highland Avenue, WIMR 6059, Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI 53705, USA; Department of Oncology/McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI 53705, USA. Electronic address:

Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphoproteomic analysis of mitotic cell extracts showed that Plk1 (L197F) and Plk1 (L197S/L211A) selectively phosphorylate Ser and Thr, respectively. Read More

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Development of a Novel Cell-Permeable Protein-Protein Interaction Inhibitor for the Polo-box Domain of Polo-like Kinase 1.

ACS Omega 2020 Jan 24;5(1):822-831. Epub 2019 Dec 24.

Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, United Kingdom.

Polo-like kinase 1 (PLK1) is a key regulator of mitosis and a recognized drug target for cancer therapy. Inhibiting the polo-box domain of PLK1 offers potential advantages of increased selectivity and subsequently reduced toxicity compared with targeting the kinase domain. However, many if not all existing polo-box domain inhibitors have been shown to be unsuitable for further development. Read More

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January 2020

Discovery of a Potent PLK1-PBD Small-Molecule Inhibitor as an Anticancer Drug Candidate through Structure-Based Design.

Molecules 2019 Nov 28;24(23). Epub 2019 Nov 28.

Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.

Polo-box domain of polo-like kinase 1 (PLK1-PBD) has a pivotal role in cell proliferation and could be implicated as a potential anticancer target. Although some small-molecule inhibitors have been developed, their clinical application has been restricted by the poor selectivity. Therefore, there is an urgent need to develop effective PLK1-PBD inhibitors. Read More

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November 2019

MCC1019, a selective inhibitor of the Polo-box domain of Polo-like kinase 1 as novel, potent anticancer candidate.

Acta Pharm Sin B 2019 Sep 10;9(5):1021-1034. Epub 2019 Feb 10.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.

Polo-like kinase (PLK1) has been identified as a potential target for cancer treatment. Although a number of small molecules have been investigated as PLK1 inhibitors, many of which showed limited selectivity. PLK1 harbors a regulatory domain, the Polo box domain (PBD), which has a key regulatory function for kinase activity and substrate recognition. Read More

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September 2019

Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold.

Eur J Med Chem 2019 Dec 11;184:111769. Epub 2019 Oct 11.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230009, China; School of Food and Biological Engineering, Hefei University of Technology, Hefei, 230009, China. Electronic address:

Polo-like kinase 1 (Plk1) is a validated target for the treatment of cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clinical studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compounds. Read More

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December 2019

Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold.

ACS Med Chem Lett 2019 Oct 13;10(10):1443-1449. Epub 2019 Sep 13.

Department of Cancer Biology, Dana Farber Cancer Institute, Boston Massachusetts 02115, United States.

Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Read More

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October 2019

A Novel Tanshinone Analog Exerts Anti-Cancer Effects in Prostate Cancer by Inducing Cell Apoptosis, Arresting Cell Cycle at G2 Phase and Blocking Metastatic Ability.

Int J Mol Sci 2019 Sep 10;20(18). Epub 2019 Sep 10.

State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.

Prostate cancer (PCa), an epithelial malignant tumor, is the second common cause of cancer death among males in western countries. Thus, the development of new strategies is urgently needed. Tanshinones isolated from and its synthetic analogs show various biological activities including anticancer effects. Read More

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September 2019

A new BET inhibitor, 171, inhibits tumor growth through cell proliferation inhibition more than apoptosis induction.

Invest New Drugs 2020 06 3;38(3):700-713. Epub 2019 Jul 3.

Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Read More

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Development of Highly Selective 1,2,3-Triazole-containing Peptidic Polo-like Kinase 1 Polo-box Domain-binding Inhibitors.

Molecules 2019 Apr 16;24(8). Epub 2019 Apr 16.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.

Members of the polo-like kinase (Plk) family of serine/threonine protein kinases play crucial roles in cell cycle regulation and proliferation. Of the five Plks (Plk1-5), Plk1 is recognized as an anticancer drug target. Plk1 contains multiple structural components that are important for its proper biological function. Read More

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A selective inhibitor of the Polo-box domain of Polo-like kinase 1 identified by virtual screening.

J Adv Res 2019 Mar 31;16:145-156. Epub 2018 Oct 31.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz 55128, Germany.

Polo-like kinase 1 (PLK1), a member of the Polo-like kinase family, plays an important regulatory role in mitosis and cell cycle progression. PLK1 overexpression is correlated with tumourigenesis and poor prognosis in cancer patients. Therefore, the identification of novel compounds that inhibit PLK1 would provide attractive therapeutic approaches. Read More

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Identification of inhibitors of the polo-box domain of polo-like kinase 1 from natural and semisynthetic compounds.

Invest New Drugs 2020 02 15;38(1):1-9. Epub 2019 Mar 15.

Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55128, Mainz, Germany.

PLK1 has an important role in the regulation of cell cycle and represents an important target for cancer treatment. This enzyme belongs to the Polo-like kinases family, which is characterized by a regulatory domain named Polo-box domain (PBD). Rather than regular kinase inhibitors, this domain provides high selectivity to PLK1. Read More

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February 2020

7-O-Methylwogonin from Scutellaria baicalensis Disturbs Mitotic Progression by Inhibiting Plk1 Activity in Hep3B Cells.

Planta Med 2019 Feb 10;85(3):217-224. Epub 2018 Sep 10.

Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Republic of Korea.

Polo-like kinase 1, a mitotic Ser/Thr kinase, has emerged as a molecular target for the development of anticancer drugs. In this study, we found that polo-like kinase 1 activity was inhibited by 7--methylwogonin and related flavones, including baicalein, dihydrobaicalein, and viscidulin II, isolated from . Although dihydrobaicalein exhibited the highest polo-like kinase 1 inhibitory activity among the four compounds, it also inhibited other kinases, such as vaccinia-related kinase 2 and polo-like kinase 2. Read More

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February 2019

Histidine N(τ)-cyclized macrocycles as a new genre of polo-like kinase 1 polo-box domain-binding inhibitors.

Bioorg Med Chem Lett 2018 10 19;28(19):3202-3205. Epub 2018 Aug 19.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA. Electronic address:

Transition toward peptide mimetics of reduced size is an important objective of peptide macrocyclization. We have previously shown that PLHSpT (2a) (where H indicates the presence of a -(CH)Ph group at the N(π) position and pT indicates phosphothreonine) is an extremely high affinity ligand of the polo-like kinase 1 (Plk1) polo-box domain (PBD). Herein we report that C-terminal macrocyclization of 2a employing N(π),N(τ)-bis-alkylated His residues as ring junctions can be achieved in a very direct fashion. Read More

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October 2018

The Meisenheimer Complex as a Paradigm in Drug Discovery: Reversible Covalent Inhibition through C67 of the ATP Binding Site of PLK1.

Cell Chem Biol 2018 09 12;25(9):1107-1116.e4. Epub 2018 Jul 12.

Cyclacel Ltd., James Lindsay Place, Dundee DD1 5JJ, UK; Drug Discovery and Biomedical Sciences, University of South Carolina, Columbia, SC 29208, USA. Electronic address:

The polo kinase family are important oncology targets that act in regulating entry into and progression through mitosis. Structure-guided discovery of a new class of inhibitors of Polo-like kinase 1 (PLK1) catalytic activity that interact with Cys67 of the ATP binding site is described. Compounds containing the benzothiazole N-oxide scaffold not only bind covalently to this residue, but are reversible inhibitors through the formation of Meisenheimer complexes. Read More

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September 2018

Design, synthesis and biological evaluation of phosphopeptides as Polo-like kinase 1 Polo-box domain inhibitors.

Bioorg Med Chem 2018 07 14;26(12):3429-3437. Epub 2018 May 14.

Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory on Protein Chemistry and Structural Biology, China Pharmaceutical University, Nanjing 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Polo-like kinase 1 (Plk1) is an anti-cancer target due to its critical role in mitotic progression. A growing body of evidence has documented that Peptide-Plk1 inhibitors showed high Plk1 binding affinity. However, phosphopeptides-Plk1 inhibitors showed poor cell membranes permeability, which limits their clinical applications. Read More

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Targeting Polo-like Kinase 1 by a Novel Pyrrole-Imidazole Polyamide-Hoechst Conjugate Suppresses Tumor Growth .

Mol Cancer Ther 2018 05 26;17(5):988-1002. Epub 2018 Feb 26.

Shenzhen Key Laboratory for Molecular Biology of Neural Development, Guangdong Key Laboratory of Nanomedicine, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.

The serine/threonine kinase Polo-like kinase 1 (Plk1) plays a pivotal role in cell proliferation and has been validated as a promising anticancer drug target. However, very limited success has been achieved in clinical applications using existing Plk1 inhibitors, due to lack of sufficient specificity toward Plk1. To develop a novel Plk1 inhibitor with high selectivity and efficacy, we designed and synthesized a pyrrole-imidazole polyamide-Hoechst conjugate, PIP3, targeted to specific DNA sequence in the promoter. Read More

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Design, synthesis, and biological evaluation of novel highly selective polo-like kinase 2 inhibitors based on the tetrahydropteridin chemical scaffold.

Eur J Med Chem 2018 Jan 23;143:724-731. Epub 2017 Nov 23.

School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui 230009, PR China. Electronic address:

Polo-like kinase 2 (Plk2) is a potential target for the treatment of cancer, which displays an important role in tumor cell proliferation and survival. In this report, according to the analysis of critical amino acid residue differences among Plk1, Plk2 and Plk3, and structure-based drug design strategies, two novel series of selective Plk2 inhibitors based on tetrahydropteridin chemical scaffold were designed and synthesized to target two specific residues, Lys86 and Tyr161 of Plk2. All compounds were evaluated for their inhibitory activity against Plk1-Plk3 and the cellular inhibition activity on six different human cancer cell lines. Read More

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January 2018

RNAi prodrugs targeting Plk1 induce specific gene silencing in primary cells from pediatric T-acute lymphoblastic leukemia patients.

J Control Release 2017 09 3;261:199-206. Epub 2017 Jul 3.

Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Sweden; Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Sweden. Electronic address:

Epidemiological studies of childhood leukemia survivors reveal an alarmingly high incidence of chronic health disabilities after treatment, therefore, more specific therapies need to be developed. Polo-like kinase 1 (Plk1) is a key player in mitosis and a target for drug development as it is upregulated in multiple cancer types. Small molecules targeting Plk1 are mainly ATP-competitors and, therefore, are known to elicit side effects due to lack of specificity. Read More

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September 2017

Discovery of a series of dihydroquinoxalin-2(1H)-ones as selective BET inhibitors from a dual PLK1-BRD4 inhibitor.

Eur J Med Chem 2017 Sep 27;137:176-195. Epub 2017 May 27.

Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address:

Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC values of 0.025 μM and 0. Read More

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September 2017

Dual Targeting of WEE1 and PLK1 by AZD1775 Elicits Single Agent Cellular Anticancer Activity.

ACS Chem Biol 2017 07 7;12(7):1883-1892. Epub 2017 Jun 7.

Drug Discovery Department, H. Lee Moffitt Cancer Center & Research Institute , Tampa, Florida 33612, United States.

Inhibition of the WEE1 tyrosine kinase enhances anticancer chemotherapy efficacy. Accordingly, the WEE1 inhibitor AZD1775 (previously MK-1775) is currently under evaluation in clinical trials for cancer in combination with chemotherapy. AZD1775 has been reported to display high selectivity and is therefore used in many studies as a probe to interrogate WEE1 biology. Read More

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Enhancing polo-like kinase 1 selectivity of polo-box domain-binding peptides.

Bioorg Med Chem 2017 Oct 28;25(19):5041-5049. Epub 2017 Feb 28.

Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States. Electronic address:

An important goal in the development of polo-like kinase 1 (Plk1) polo-box domain (PBD) binding inhibitors is selectivity for Plk1 relative to Plk2 and Plk3. In our current work we show that Plk1 PBD selectivity can be significantly enhanced by modulating interactions within a previously discovered "cryptic pocket" and a more recently identified proximal "auxiliary pocket." Read More

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October 2017

Phosphatase-Stable Phosphoamino Acid Mimetics That Enhance Binding Affinities with the Polo-Box Domain of Polo-like Kinase 1.

ChemMedChem 2017 02 9;12(3):202-206. Epub 2017 Jan 9.

Chemical Biology Laboratory, National Cancer Institute, National Institutes of Health, 1050 Boyles Street, Frederick, MD, 21702, USA.

(2S,3R)-2-Amino-3-methyl-4-phosphonobutanoic acid (Pmab) is a phosphatase-stable analogue of phosphothreonine (pThr), which has been used in a variety of biological contexts. Among these applications are peptidomimetic ligands that bind to the polo-box domain (PBD) of polo-like kinase 1 (Plk1) with affinities approaching that of the corresponding pThr-containing peptides. However, Pmab is not widely used, because there are no direct, high-yield preparations of suitably protected reagent. Read More

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February 2017

Designed inhibitor for nuclear localization signal of polo-like kinase 1 induces mitotic arrest.

Chem Biol Drug Des 2017 05 24;89(5):732-740. Epub 2016 Nov 24.

Center for Quantitative Biology, Peking University, Beijing, China.

Polo-like kinase 1 (Plk1), a member of polo-like kinase family, regulates multiple essential steps of the cell cycle progression. Plk1 is overexpressed in multiple cancer cell lines and considered to be a prime anticancer target. Plk1 accumulates in the nucleus during S and G2 phases by its bipartite nuclear localization signal (NLS) sequence, which is crucial for Plk1 regulation during normal cell cycle progression. Read More

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Identification of Polo-like kinase 1 interaction inhibitors using a novel cell-based assay.

Sci Rep 2016 11 22;5:37581. Epub 2016 Nov 22.

Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Canada.

Polo-like kinase 1 (Plk1) plays several roles in cell division and it is a recognized cancer drug target. Plk1 levels are elevated in cancer and several types of cancer cells are hypersensitive to Plk1 inhibition. Small molecule inhibitors of the kinase domain (KD) of Plk1 have been developed. Read More

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November 2016