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Polo-like kinase

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https://www.readbyqxmd.com/read/28212994/an-open-label-phase-ii-study-of-the-polo-like-kinase-1-plk-1-inhibitor-bi-2536-in-patients-with-relapsed-small-cell-lung-cancer-sclc
#1
Mark M Awad, Quincy S-C Chu, Leena Gandhi, Joe J Stephenson, Ramaswamy Govindan, Daniel S Bradford, Philip D Bonomi, David M Ellison, Keith D Eaton, Holger Fritsch, Gerd Munzert, Bruce E Johnson, Mark A Socinski
OBJECTIVES: This phase II, open-label study was designed to evaluate the response rate to the polo-like kinase 1 (Plk-1) inhibitor BI 2536 in patients with sensitive-relapsed small cell lung cancer (SCLC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety. MATERIALS AND METHODS: Patients were treated with the recommended phase II dose of 200mg of BI 2536 intravenously every 21days. This was a two-stage design with an early stopping rule in place if responses were not seen in at least 2 of the first 18 enrolled patients...
February 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/28185436/corrigendum-phosphatase-stable-phosphoamino-acid-mimetics-that-enhance-binding-affinities-with-the-polo-box-domain-of-polo-like-kinase%C3%A2-1
#2
David Hymel, Terrence R Burke
No abstract text is available yet for this article.
February 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28184925/inhibiting-plk1-induces-autophagy-of-acute-myeloid-leukemia-cells-via-mammalian-target-of-rapamycin-pathway-dephosphorylation
#3
Yan-Fang Tao, Zhi-Heng Li, Wei-Wei Du, Li-Xiao Xu, Jun-Li Ren, Xiao-Lu Li, Fang Fang, Yi Xie, Mei Li, Guang-Hui Qian, Yan-Hong Li, Yi-Ping Li, Gang Li, Yi Wu, Xing Feng, Jian Wang, Wei-Qi He, Shao-Yan Hu, Jun Lu, Jian Pan
Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy‑inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis...
March 2017: Oncology Reports
https://www.readbyqxmd.com/read/28169164/structure-based-design-and-sar-development-of-5-6-dihydroimidazolo-1-5-f-pteridine-derivatives-as-novel-polo-like-kinase-1-inhibitors
#4
Andre Kiryanov, Srinivasa Natala, Benjamin Jones, Christopher McBride, Victoria Feher, Betty Lam, Yan Liu, Kouhei Honda, Noriko Uchiyama, Tomohiro Kawamoto, Yuichi Hikichi, Lilly Zhang, David Hosfield, Robert Skene, Hua Zou, Jeffrey Stafford, Xiaodong Cao, Takashi Ichikawa
Using structure-based drug design, we identified a novel series of 5,6-dihydroimidazolo[1,5-f]pteridine PLK1 inhibitors. Rational improvements to compounds of this class resulted in single-digit nanomolar enzyme and cellular activity against PLK1, and oral bioavailability. Compound 1 exhibits >7 fold induction of phosphorylated Histone H3 and is efficacious in an in vivo HT-29 tumor xenograft model.
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28154193/dissecting-the-molecular-pathway-involved-in-plk2-mediated-%C3%AE-synuclein-selective-autophagic-degradation
#5
Manel Dahmene, Morgan Bérard, Abid Oueslati
Increasing lines of evidence support the causal link between α-synuclein (α-syn) accumulation in the brain and Parkinson disease (PD) pathogenesis. Therefore, lowering α-syn protein levels may represent a viable therapeutic strategy for the treatment of PD and related disorders. We recently described a novel selective α-syn degradation pathway, catalyzed by the activity of the Polo-like kinase 2 (PLK2), capable of reducing α-syn protein expression and suppressing its toxicity in vivo. However, the exact molecular mechanisms underlying this degradation route remain elusive...
January 30, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28138033/targeted-treatment-of-metastatic-breast-cancer-by-plk1-sirna-delivered-by-an-antioxidant-nanoparticle-platform
#6
Jingga Morry, Worapol Ngamcherdtrakul, Shenda Gu, Moataz Reda, David J Castro, Thanapon Sangvanich, Joe W Gray, Wassana Yantasee
Metastatic breast cancer is developed in about 20-30% of newly diagnosed early stage breast cancer patients despite treatments. Herein, we report a novel nanoparticle platform with intrinsic anti-metastatic properties for the targeted delivery of Polo-like kinase 1 siRNA (siPLK1). We first evaluated it in a triple negative breast cancer (TNBC) model, which shows high metastatic potential. PLK1 was identified as the top therapeutic target for TNBC cells and tumor initiating cells in a kinome-wide screen. The platform consists of a 50-nm mesoporous silica nanoparticle (MSNP) core coated layer-by-layer with bioreducible cross-linked PEI and PEG polymers, conjugated with an antibody for selective uptake into cancer cells...
January 30, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28127048/cell-cycle-proteins-as-promising-targets-in-cancer-therapy
#7
REVIEW
Tobias Otto, Piotr Sicinski
Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle...
27, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28126323/mutations-of-the-lim-protein-ajuba-mediate-sensitivity-of-head-and-neck-squamous-cell-carcinoma-to-treatment-with-cell-cycle-inhibitors
#8
Ming Zhang, Ratnakar Singh, Shaohua Peng, Tuhina Mazumdar, Vaishnavi Sambandam, Li Shen, Pan Tong, Lerong Li, Nene Kalu, Curtis R Pickering, Mitchell Frederick, Jeffrey N Myers, Jing Wang, Faye M Johnson
The genomic alterations identified in head and neck squamous cell carcinoma (HNSCC) tumors have not resulted in any changes in clinical care, making the development of biomarker-driven targeted therapy for HNSCC a major translational gap in knowledge. To fill this gap, we used 59 molecularly characterized HNSCC cell lines and found that mutations of AJUBA, SMAD4 and RAS predicted sensitivity and resistance to treatment with inhibitors of polo-like kinase 1 (PLK1), checkpoint kinases 1 and 2, and WEE1. Inhibition or knockdown of PLK1 led to cell-cycle arrest at the G2/M transition and apoptosis in sensitive cell lines and decreased tumor growth in an orthotopic AJUBA-mutant HNSCC mouse model...
January 23, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28102733/plk1-polo-like-kinase-1-inhibits-mtor-complex-1-and-promotes-autophagy
#9
Stefanie Ruf, Alexander Martin Heberle, Miriam Langelaar-Makkinje, Sara Gelino, Deepti Wilkinson, Carolin Gerbeth, Jennifer Jasmin Schwarz, Birgit Holzwarth, Bettina Warscheid, Chris Meisinger, Marcel A T M van Vugt, Ralf Baumeister, Malene Hansen, Kathrin Thedieck
Mechanistic target of rapamycin complex 1 (MTORC1) and PLK1 (polo like kinase 1) are major drivers of cancer cell growth and proliferation, and inhibitors of both protein kinases are currently being investigated in clinical studies. To date, MTORC1's and PLK1's functions are mostly studied separately, and reports on their mutual crosstalk are scarce. Here, we identify PLK1 as a physical MTORC1 interactor in human cancer cells. PLK1 inhibition enhances MTORC1 activity under nutrient sufficiency and in starved cells, and PLK1 directly phosphorylates the MTORC1 component RPTOR/RAPTOR in vitro...
January 19, 2017: Autophagy
https://www.readbyqxmd.com/read/28074435/plk1-inhibition-leads-to-a-failure-of-mitotic-division-during-the-first-mitotic-division-in-pig-embryos
#10
Zixiao Zhang, Changchao Chen, Panpan Cui, Yaya Liao, Lingyun Yao, Yue Zhang, Rong Rui, Shiqiang Ju
PURPOSE: This study was conducted to examine the dynamic distribution of polo-like 1 kinase (Plk1) and the possible role it plays in first mitotic division during early porcine embryo development. METHODS: Indirect immunofluorescence and confocal microscopy imaging techniques combined with western blot analyses were used to study the dynamic expression and subcellular localization of Plk1 protein in pig parthenogenetic embryos. Finally, a selective Plk1 inhibitor, GSK461364, was used to evaluate the potential role of Plk1 during this special stage...
January 10, 2017: Journal of Assisted Reproduction and Genetics
https://www.readbyqxmd.com/read/28069876/targeting-plk1-to-enhance-efficacy-of-olaparib-in-castration-resistant-prostate-cancer
#11
Jie Li, Ruixin Wang, Yifan Kong, Meaghan M Broman, Colin Carlock, Long Chen, Zhiguo Li, Elia Farah, Timothy L Ratliff, Xiaoqi Liu
Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors...
January 9, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28069132/molecular-regulation-of-the-spindle-assembly-checkpoint-by-kinases-and-phosphatases
#12
G Manic, F Corradi, A Sistigu, S Siteni, I Vitale
The spindle assembly checkpoint (SAC) is a surveillance mechanism contributing to the preservation of genomic stability by monitoring the microtubule attachment to, and/or the tension status of, each kinetochore during mitosis. The SAC halts metaphase to anaphase transition in the presence of unattached and/or untensed kinetochore(s) by releasing the mitotic checkpoint complex (MCC) from these improperly-oriented kinetochores to inhibit the anaphase-promoting complex/cyclosome (APC/C). The reversible phosphorylation of a variety of substrates at the kinetochore by antagonistic kinases and phosphatases is one major signaling mechanism for promptly turning on or turning off the SAC...
2017: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/28061448/targeting-basal-like-breast-tumors-with-bromodomain-and-extraterminal-domain-bet-and-polo-like-kinase-inhibitors
#13
Cristina Nieto-Jiménez, Ana Alcaraz-Sanabria, Javier Pérez-Peña, Verónica Corrales-Sánchez, Gemma Serrano-Heras, Eva M Galán-Moya, Leticia Serrano-Oviedo, Juan Carlos Montero, Miguel Burgos, Juan Llopis, Atanasio Pandiella, Alberto Ocaña
Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors...
January 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28052114/crl4wdr1-controls-polo-like-kinase-protein-abundance-to-promote-bilobe-duplication-basal-body-segregation-and-flagellum-attachment-in-trypanosoma-brucei
#14
Huiqing Hu, Qing Zhou, Xianxian Han, Ziyin Li
The Polo-like kinase homolog in Trypanosoma brucei, TbPLK, plays essential roles in basal body segregation, flagellum attachment and cytokinesis. The level of TbPLK protein is tightly controlled, but the underlying mechanism remains elusive. Here, we report a Cullin-RING ubiquitin ligase composed of Cullin4, the DNA damage-binding protein 1 homolog TbDDB1 and a WD40-repeat protein WDR1 that controls TbPLK abundance in the basal body and the bilobe. WDR1, through its C-terminal domain, interacts with the PEST motif in TbPLK and, through its N-terminal WD40 motif, binds to TbDDB1...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28036269/the-gsk461364-plk1-inhibitor-exhibits-strong-antitumoral-activity-in-preclinical-neuroblastoma-models
#15
Kristian W Pajtler, Natalie Sadowski, Sandra Ackermann, Kristina Althoff, Kerstin Schönbeck, Katharina Batzke, Simon Schäfers, Andrea Odersky, Lukas Heukamp, Kathy Astrahantseff, Annette Künkele, Hedwig E Deubzer, Alexander Schramm, Annika Sprüssel, Theresa Thor, Sven Lindner, Angelika Eggert, Matthias Fischer, Johannes H Schulte
Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models...
January 24, 2017: Oncotarget
https://www.readbyqxmd.com/read/28030843/targeted-delivery-of-crispr-cas9-to-prostate-cancer-by-modified-grna-using-a-flexible-aptamer-cationic-liposome
#16
Shuai Zhen, Y Takahashi, S Narita, Yi-Chen Yang, Xu Li
The potent ability of CRISPR/Cas9 system to inhibit the expression of targeted gene is being exploited as a new class of therapeutics for a variety of diseases. However, the efficient and safe delivery of CRISPR/Cas9 into specific cell populations is still the principal challenge in the clinical development of CRISPR/Cas9 therapeutics. In this study, a flexible aptamer-liposome-CRISPR/Cas9 chimera was designed to combine efficient delivery and increased flexibility. Our chimera incorporated an RNA aptamer that specifically binds prostate cancer cells expressing the prostate-specific membrane antigen as a ligand...
December 21, 2016: Oncotarget
https://www.readbyqxmd.com/read/27992122/phosphatase-stable-phosphoamino-acid-mimetics-that-enhance-binding-affinities-with-the-polo-box-domain-of-polo-like-kinase%C3%A2-1
#17
David Hymel, Terrence R Burke
(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. We have now achieved an efficient synthesis of protected Pmab, as well as variants with different substituents at the 3R center...
February 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/27979967/daz-interacting-protein-1-dzip1-phosphorylation-by-polo-like-kinase-1-plk1-regulates-the-centriolar-satellite-localization-of-the-bbsome-protein-during-the-cell-cycle
#18
Boyan Zhang, Gang Wang, Xiaowei Xu, Sisi Yang, Tenghan Zhuang, Guopeng Wang, He Ren, Steven Y Cheng, Qing Jiang, Chuanmao Zhang
The function of the primary cilia, which is assembled in most vertebrate cells, is achieved by transport in and out of kinds of signaling receptors. The BBSome protein complex could recognize and target membrane proteins to the cilia, but how the BBSome itself is transported into the cilia is poorly understood. Here we demonstrate that the centrosome protein Dzip1 mediates the assembly of the BBSome-Dzip1-PCM1 complex in the centriolar satellites (CS) at the G0 phase for ciliary translocation of the BBSome...
January 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27965913/blood-plasma-of-patients-with-parkinson-s-disease-increases-alpha-synuclein-aggregation-and-neurotoxicity
#19
Peng Wang, Xin Li, Xuran Li, Weiwei Yang, Shun Yu
A pathological hallmark of Parkinson's disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn...
2016: Parkinson's Disease
https://www.readbyqxmd.com/read/27965426/mitotic-phosphotyrosine-network-analysis-reveals-that-tyrosine-phosphorylation-regulates-polo-like-kinase-1-plk1
#20
Danielle Caron, Dominic P Byrne, Philippe Thebault, Denis Soulet, Christian R Landry, Patrick A Eyers, Sabine Elowe
Tyrosine phosphorylation is closely associated with cell proliferation. During the cell cycle, serine and threonine phosphorylation plays the leading role, and such phosphorylation events are most dynamic during the mitotic phase of the cell cycle. However, mitotic phosphotyrosine is not well characterized. Although a few functionally-relevant mitotic phosphotyrosine sites have been characterized, evidence suggests that this modification may be more prevalent than previously appreciated. Here, we examined tyrosine phosphorylation in mitotic human cells including those on spindle-associated proteins...
December 13, 2016: Science Signaling
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