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https://www.readbyqxmd.com/read/28314279/comparative-analysis-of-a-fret-based-plk1-kinase-assay-to-identify-plk1-inhibitors-for-chemotherapy
#1
Sol-Bi Shin, Sang-Uk Woo, Young-Joo Lee, Hyungshin Yim
Advanced techniques for detecting kinase inhibitors are in demand due to limitations of traditional approaches. Here, we used a fluorescence resonance energy transfer (FRET)-based kinase assay, a sensitive fluorescence turn-on biosensing platform, to identify a Polo-like kinase 1 (PLK1) inhibitor. The assay was developed with the Z'-Lyte™ FRET-peptide and PLK1 kinase purified from a baculovirus expression system. Using PLK1 inhibitors, sensitivity and efficiency of this FRET-based PLK1 kinase assay were compared to those of radioisotope-based and immunoblot-based assays...
March 2017: Anticancer Research
https://www.readbyqxmd.com/read/28296906/anticancer-activity-of-a-novel-small-molecule-tubulin-inhibitor-stk899704
#2
Krisada Sakchaisri, Sun-Ok Kim, Joonsung Hwang, Nak Kyun Soung, Kyung Ho Lee, Tae Woong Choi, Yongjun Lee, Chan-Mi Park, Naraganahalli R Thimmegowda, Phil Young Lee, Bettaswamigowda Shwetha, Ganipisetti Srinivasrao, Thi Thu Huong Pham, Jae-Hyuk Jang, Hye-Won Yum, Young-Joon Surh, Kyung S Lee, Hwangseo Park, Seung Jun Kim, Yong Tae Kwon, Jong Seog Ahn, Bo Yeon Kim
We have identified the small molecule STK899704 as a structurally novel tubulin inhibitor. STK899704 suppressed the proliferation of cancer cell lines from various origins with IC50 values ranging from 0.2 to 1.0 μM. STK899704 prevented the polymerization of purified tubulin in vitro and also depolymerized microtubule in cultured cells leading to mitotic arrest, associated with increased Cdc25C phosphorylation and the accumulation of both cyclin B1 and polo-like kinase 1 (Plk1), and apoptosis. Unlike many anticancer drugs such as Taxol and doxorubicin, STK899704 effectively displayed antiproliferative activity against multidrug-resistant cancer cell lines...
2017: PloS One
https://www.readbyqxmd.com/read/28296169/pyrrole-based-macrocyclic-small-molecule-inhibitors-targeting-oocyte-maturation
#3
Jeong Kyu Bang, Pethaiah Gunasekaran, So Rim Lee, Seung-Min Jeong, Jeong-Woo Kwon, Toshiki Takei, Yuya Asahina, Geul Bang, Seongnyeon Kim, Mija Ahn, Eun Kyung Ryu, Hak Nam Kim, Ki-Yub Nam, Song Yub Shin, Hironobu Hojo, Suk Namgoong, Nam-Hyung Kim
Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic AB103-8 that targets polo box domain (PBD) of PLK1 affected oocyte meiotic maturation and meiosis resumption. However, to overcome the peptidic drawbacks, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and screened against porcine oocyte maturation rates. Among them, compound 4 showed the highest inhibitory activity with enhanced inhibition against the embryos blastocyst formation...
March 12, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28287096/blockade-of-vascular-endothelial-growth-factor-receptors-by-tivozanib-has-potential-anti-tumour-effects-on-human-glioblastoma-cells
#4
Majid Momeny, Farima Moghaddaskho, Narges K Gortany, Hassan Yousefi, Zahra Sabourinejad, Ghazaleh Zarrinrad, Shahab Mirshahvaladi, Haniyeh Eyvani, Farinaz Barghi, Leila Ahmadinia, Mahmoud Ghazi-Khansari, Ahmad R Dehpour, Saeid Amanpour, Seyyed M Tavangar, Leila Dardaei, Amir H Emami, Kamran Alimoghaddam, Ardeshir Ghavamzadeh, Seyed H Ghaffari
Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C...
March 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28286049/insulin-signaling-regulates-the-foxm1-plk1-cenp-a-pathway-to-promote-adaptive-pancreatic-%C3%AE-%C3%A2-cell-proliferation
#5
Jun Shirakawa, Megan Fernandez, Tomozumi Takatani, Abdelfattah El Ouaamari, Prapaporn Jungtrakoon, Erin R Okawa, Wei Zhang, Peng Yi, Alessandro Doria, Rohit N Kulkarni
Investigation of cell-cycle kinetics in mammalian pancreatic β cells has mostly focused on transition from the quiescent (G0) to G1 phase. Here, we report that centromere protein A (CENP-A), which is required for chromosome segregation during the M-phase, is necessary for adaptive β cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1 to regulate expression of CENP-A and polo-like kinase-1 (PLK1) by modulating cyclin-dependent kinase-1/2. CENP-A deposition at the centromere is augmented by PLK1 to promote mitosis, while knocking down CENP-A limits β cell proliferation and survival...
February 26, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28285924/enhancing-polo-like-kinase-1-selectivity-of-polo-box-domain-binding-peptides
#6
Xue Zhi Zhao, David Hymel, Terrence R Burke
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."
February 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28283778/plk1-associated-micrornas-are-correlated-with-pediatric-medulloblastoma-prognosis
#7
Julia Alejandra Pezuk, María Sol Brassesco, Ricardo Santos de Oliveira, Hélio Rubens Machado, Luciano Neder, Carlos Alberto Scrideli, Luiz Gonzaga Tone
PURPOSE: Medulloblastoma (MB) is the most common malignant tumor of the central nervous system (CNS) in children. Despite its relative good survival rates, treatment can cause long time sequels and may impair patients' lifespan and quality, making the search for new treatment options still necessary. Polo like kinases (PLKs) constitute a five-member serine/threonine kinases family (PLK 1-5) that regulates different stages during cell cycle. Abnormal PLKs expression has been observed in several cancer types, including MB...
March 10, 2017: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
https://www.readbyqxmd.com/read/28274274/a-novel-form-of-necrosis-triad-occurs-in-human-huntington-s-disease
#8
Emiko Yamanishi, Kazuko Hasegawa, Kyota Fujita, Shizuko Ichinose, Saburo Yagishita, Miho Murata, Kazuhiko Tagawa, Takumi Akashi, Yoshinobu Eishi, Hitoshi Okazawa
We previously reported transcriptional repression-induced atypical cell death of neuron (TRIAD), a new type of necrosis that is mainly regulated by Hippo pathway signaling and distinct from necroptosis regulated by RIP1/3 pathway. Here, we examined the ultrastructural and biochemical features of neuronal cell death in the brains of human HD patients in parallel with the similar analyses using mutant Htt-knock-in (Htt-KI) mice. LATS1 kinase, the critical regulator and marker of TRIAD, is actually activated in cortical neurons of postmortem human HD and of Htt-KI mouse brains, while apoptosis promoter kinase Plk1 was inactivated in human HD brains...
March 8, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28272965/regulation-of-4e-bp1-activity-in-the-mammalian-oocyte
#9
Denisa Jansova, Marketa Koncicka, Anna Tetkova, Renata Cerna, Radek Malik, Edgar Del Llano, Michal Kubelka, Andrej Susor
Fully grown mammalian oocytes utilize transcripts synthetized and stored during earlier development. RNA localization followed by a local translation is a mechanism responsible for the regulation of spatial and temporal gene expression. Here we show that the mouse oocyte contains three forms of cap-dependent translational repressor expressed on the mRNA level: 4E-BP1, 4E-BP2 and 4E-BP3. However, only 4E-BP1 is present as a protein in oocytes, it becomes inactivated by phosphorylation after nuclear envelope breakdown and as such it promotes cap-dependent translation after NEBD...
March 8, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28270075/comparative-effects-of-polo-like-kinase-1-inhibitors-as-monotherapy-and-in-combination-with-current-treatments-for-medulloblastoma
#10
Julia Alejandra Pezuk, Maria Sol Brassesco, Priscila Maria Manzini Ramos, Carlos Alberto Scrideli, Luiz Gonzaga Tone
BACKGROUND: Medulloblastoma (MB) is one of most frequent malignant tumors that affects children. Despite relative good survival rates, long time sequels are still significant and represent a challenge for treatment of MB patients. Therefore, in an attempt to reduce treatment aftereffects new therapeutic targets are constantly being explored. Polo like kinase 1 (PLK1) is a master cell cycle regulator that has been reported increased in proliferative cells, while its depletion has been repeatedly proposed as an oncological therapeutic strategy...
February 13, 2017: Anti-cancer Agents in Medicinal Chemistry
https://www.readbyqxmd.com/read/28267710/dasatinib-synergises-with-irinotecan-to-suppress-hepatocellular-carcinoma-via-inhibiting-the-protein-synthesis-of-plk1
#11
Li Xu, Yuanrun Zhu, Jinjin Shao, Min Chen, Hao Yan, Guanqun Li, Yi Zhu, Zhifei Xu, Bo Yang, Peihua Luo, Qiaojun He
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of malignant tumour and has poor prognosis. Currently, systematic chemotherapy is the only approach to prolong survival. Thus the development of new treatment regimens is urgently needed to improve the therapeutic efficacy. Our study intended to assess the combination of dasatinib and irinotecan against HCC and made an effort to develop a potential medical choice for advanced HCC patients. METHODS: We used SRB colorimetric assay and clonogenic assay to assess antitumour effect in vitro and HCC xenograft model to assess antitumour effect in vivo...
March 7, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28235541/targeted-knockdown-of-polo-like-kinase-1-alters-metabolic-regulation-in-melanoma
#12
Rosie Elizabeth Ann Gutteridge, Chandra K Singh, Mary Ann Ndiaye, Nihal Ahmad
A limited number of studies have indicated an association of the mitotic kinase polo-like kinase 1 (PLK1) and cellular metabolism. Here, employing an inducible RNA interference approach in A375 melanoma cells coupled with a PCR array and multiple validation approaches, we demonstrated that PLK1 alters a number of genes associated with cellular metabolism. PLK1 knockdown resulted in a significant downregulation of IDH1, PDP2 and PCK1 and upregulation of FBP1. Ingenuity Pathway Analysis (IPA) identified that 1) glycolysis and the pentose phosphate pathway are major canonical pathways associated with PLK1, and 2) PLK1 inhibition-modulated genes were largely associated with cellular proliferation, with FBP1 being the key modulator...
February 22, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28193847/dna-damage-response-independent-role-for-mdc1-in-maintaining-genomic-stability
#13
Zhiguo Li, Chen Shao, Yifan Kong, Colin Carlock, Nihal Ahmad, Xiaoqi Liu
MDC1 is a central player in checkpoint activation and subsequent DNA repair following DNA damage. Although MDC1 has been extensively studied, much of its known functions to date pertains to the DNA damage response (DDR) pathway. Herein, we report a novel function of phosphorylated MDC1, independent of ATM and DNA damage, which is required for proper mitotic progression and maintenance of genomic stability. We demonstrate that MDC1 is an in vivo target of Plk1 and that the phosphorylated MDC1 is dynamically localized to nuclear envelopes, centrosomes, kinetochores and the midbodies...
February 13, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28192620/ypc-21661-and-ypc-22026-novel-small-molecules-inhibit-znf143-activity-in-vitro-and-in-vivo
#14
Hirotaka Haibara, Ryuta Yamazaki, Yukiko Nishiyama, Masahiro Ono, Tsuneyuki Kobayashi, Atsuko Hokkyo-Itagaki, Fukiko Nishisaka, Hiroyuki Nishiyama, Akinobu Kurita, Takeshi Matsuzaki, Hiroto Izumi, Kimitoshi Kohno
Zinc-finger protein 143 (ZNF143) is a transcription factor that is involved in anticancer drug resistance and cancer cell survival. In the present study, we identified a novel small molecule N-(5-bromo-2-methoxyphenyl)-3-(pyridine-3-yl) propiolamide (YPC-21661) that inhibited ZNF143 promoter activity and down-regulated the expression of the ZNF143-regulated genes, RAD51, PLK1, and Survivin, by inhibiting the binding of ZNF143 to DNA. In addition, YPC-21661 was cytotoxic and induced apoptosis in the human colon cancer cell line, HCT116 and human prostate cancer cell line, PC-3...
February 13, 2017: Cancer Science
https://www.readbyqxmd.com/read/28188792/recruitment-of-pp1-to-the-centrosomal-scaffold-protein-cep192
#15
Isha Nasa, Laura Trinkle-Mulcahy, P Douglas, Sibapriya Chaudhuri, S P Lees-Miller, Kyung S Lee, Greg B Moorhead
Centrosomal protein of 192 kDa (CEP192) is a scaffolding protein that recruits the mitotic protein kinases Aurora A and PLK1 to the centrosome. Here we demonstrate that CEP192 also recruits the type one protein phosphatase (PP1) via a highly conserved KHVTF docking motif. The threonine of the KHVTF motif is phosphorylated during mitosis and protein kinase inhibition studies suggest this to be a PLK1-dependent process.
February 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28188342/the-equilibrium-of-ubiquitination-and-deubiquitination-at-plk1-regulates-sister-chromatid-separation
#16
REVIEW
Junjun Liu, Chuanmao Zhang
PLK1 regulates almost every aspect of mitotic events, including mitotic entry, spindle assembly, chromosome alignment, sister chromatid segregation, metaphase-anaphase transition, cytokinesis, etc. In regulating the chromosome alignment and sister chromatid segregation, PLK1 has to be localized to and removed from kinetochores at the right times, and the underlying mechanism that regulates PLK1 both spatially and temporally only became clearer recently. It has been found that deubiquitination and ubiquitination of PLK1 are responsible for its localization to and dissociation from the kinetochores, respectively...
February 10, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/28184925/inhibiting-plk1-induces-autophagy-of-acute-myeloid-leukemia-cells-via-mammalian-target-of-rapamycin-pathway-dephosphorylation
#17
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/28178660/plk1-inhibition-enhances-temozolomide-efficacy-in-idh1-mutant-gliomas
#18
Robert F Koncar, Zhengtao Chu, Lindsey E Romick-Rosendale, Susanne I Wells, Timothy A Chan, Xiaoyang Qi, El Mustapha Bahassi
Despite multimodal therapy with radiation and the DNA alkylating agent temozolomide (TMZ), malignant gliomas remain incurable. Up to 90% of grades II-III gliomas contain a single mutant isocitrate dehydrogenase 1 (IDH1) allele. IDH1 mutant-mediated transformation is associated with TMZ resistance; however, there is no clinically available means of sensitizing IDH1 mutant tumors to TMZ. In this study we sought to identify a targetable mechanism of TMZ resistance in IDH1 mutant tumors to enhance TMZ efficacy...
February 2, 2017: Oncotarget
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
#19
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/28152267/redox-activatable-atp-depleting-micelles-with-dual-modulation-characteristics-for-multidrug-resistant-cancer-therapy
#20
Hebin Wang, Yang Li, Miaozun Zhang, Di Wu, Youqing Shen, Guping Tang, Yuan Ping
A fast adenosine triphosphate (ATP)-depleting micellar system that is activated by intracellular redox for the codelivery of anticancer drug paclitaxel (PTX) and small interference RNA (siRNA) targeting polo-like kinase1 (PLK1) is developed to address the key challenges of multidrug-resistant (MDR) cancer therapy. The ATP-depleting micelle is self-assembled from a redox-responsive amphiphilic polymer (termed as bPEG-SS-P123-PEI (PSPP)) that is composed of biocompatible branched polyethylene glycol (PEG) with 8 arms (bPEG), ATP-depleting Pluronic P123 (P123), and cationic low molecular weight polyethylenimine (PEI) blocks...
February 2, 2017: Advanced Healthcare Materials
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