17 results match your criteria orally plk1

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A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia.

Clin Cancer Res 2020 12 30;26(23):6132-6140. Epub 2020 Sep 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Purpose: The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase Ib study of the PLK1 inhibitor, onvansertib, in combination with either low-dose cytarabine (LDAC) or decitabine in patients with relapsed or refractory (R/R) AML.

Patients And Methods: Onvansertib was administered orally, in escalating doses, on days 1-5 in combination with either LDAC (20 mg/m; days 1-10) or decitabine (20 mg/m; days 1-5) in a 28-day cycle. Read More

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December 2020

Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations.

Cancers (Basel) 2019 Jun 13;11(6). Epub 2019 Jun 13.

CEINGE Biotecnologie Avanzate, 80145 Naples, Italy.

Wee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1, alone or in combination with DNA damaging agents, can kill cancer cells by mitotic catastrophe, a tumor suppressive response that follows mitosis onset in the presence of under-replicated or damaged DNA. Read More

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Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma.

Cancer Lett 2019 03 4;445:24-33. Epub 2019 Jan 4.

Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany; German Consortium for Translational Cancer Research (DKTK), Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany. Electronic address:

Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Read More

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Identification of novel genes involved in gingival epithelial cells responding to Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis infections.

Arch Oral Biol 2018 Dec 30;96:113-121. Epub 2018 Aug 30.

Department of Dentistry, Weifang People's Hospital, Weifang Medical University, Weifang, 261041, China. Electronic address:

Objective: This study aimed to identify the differentially expressed genes (DEGs) in gingiva epithelial cells responding to Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis infections using bioinformatics method.

Study Design: GSE9723 dataset was downloaded from Gene Expression Omnibus, and DEGs between the infected cells and controls were identified using unpaired t-test. Overlapping DEGs in responding to Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis infections were extracted. Read More

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December 2018

Immunohistochemical expression of polo-like kinase 1 in oral squamous cell carcinoma and oral submucous fibrosis.

Indian J Dent Res 2018 Mar-Apr;29(2):171-175

Department of Pathology, Tagore Medical College and Hospital, Chennai, Tamil Nadu, India.

Context: Polo-like kinase 1 (PLK1) is a critical molecule in the proliferation of several human cancers. Overexpression of PLK1 has been correlated with cancer cell proliferation and lower overall survival rates. Although PLK1 has been studied in various tumors, information regarding its expression in oral cancer and precancer is limited. Read More

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November 2018

Identification of the hot spot residues for pyridine derivative inhibitor CCT251455 and ATP substrate binding on monopolar spindle 1 (MPS1) kinase by molecular dynamic simulation.

J Biomol Struct Dyn 2019 Feb 8;37(3):611-622. Epub 2018 Mar 8.

a Collaborative Innovation Center of Chemistry for Life Sciences, Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences , University of Sciences and Technology of China , Hefei , 230027 , P. R. China.

Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. Read More

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February 2019

Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors.

Invest New Drugs 2018 02 20;36(1):85-95. Epub 2017 Jul 20.

Virginia G. Piper Cancer Centers at Scottsdale Healthcare, Scottsdale, AZ, USA.

Background Pharmacological inhibition of polo-like kinase 1 (PLK1) represents a new approach for the treatment of solid tumors. This study was aimed at determining the first cycle dose-limiting toxicities (DLTs) and related maximum tolerated dose (MTD) of NMS-1286937, a selective ATP-competitive PLK1-specific inhibitor. Secondary objectives included evaluation of its safety and pharmacokinetic (PK) profile in plasma, its antitumor activity, and its ability to modulate intracellular targets in biopsied tissue. Read More

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February 2018

ER maleate is a novel anticancer agent in oral cancer: implications for cancer therapy.

Oncotarget 2016 Mar;7(13):17162-81

Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.

ER maleate [10-(3-Aminopropyl)-3, 4-dimethyl-9(10H)-acridinone maleate] identified in a kinome screen was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC). Our aim was to demonstrate its anticancer effects, identify putative molecular targets and determine their clinical relevance and investigate its chemosensitization potential for platinum drugs to aid in OSCC management. Biologic effects of ER maleate were determined using oral cancer cell lines in vitro and oral tumor xenografts in vivo. Read More

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A phase I, dose-escalation study of volasertib combined with nintedanib in advanced solid tumors.

Ann Oncol 2015 Nov 22;26(11):2341-6. Epub 2015 Sep 22.

Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of New Drugs Development, European Institute of Oncology, Milan, Italy.

Background: Volasertib is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study determined the maximum tolerated dose (MTD) and pharmacokinetics of volasertib combined with nintedanib, a potent and orally bioavailable triple angiokinase inhibitor, in patients with advanced solid tumors.

Patients And Methods: This open-label, dose-escalation trial recruited patients with advanced metastatic solid tumors following failure of conventional treatment (NCT01022853; Study 1230. Read More

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November 2015

Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1).

Bioorg Med Chem Lett 2013 Jun 27;23(12):3662-6. Epub 2013 Feb 27.

Takeda California, 10410 Science Center Drive, San Diego, CA 92121, USA.

Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. Read More

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NMS-P937, an orally available, specific small-molecule polo-like kinase 1 inhibitor with antitumor activity in solid and hematologic malignancies.

Mol Cancer Ther 2012 Apr 7;11(4):1006-16. Epub 2012 Feb 7.

Nerviano Medical Sciences Srl, Nerviano, Milan, Italy.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase considered to be the master player of cell-cycle regulation during mitosis. It is indeed involved in centrosome maturation, bipolar spindle formation, chromosome separation, and cytokinesis. PLK1 is overexpressed in a variety of human tumors and its overexpression often correlates with poor prognosis. Read More

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TAK-960, a novel, orally available, selective inhibitor of polo-like kinase 1, shows broad-spectrum preclinical antitumor activity in multiple dosing regimens.

Mol Cancer Ther 2012 Mar 21;11(3):700-9. Epub 2011 Dec 21.

Takeda Pharmaceutical Company Ltd., 26-1 Muraoka Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. TAK-960 [4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl) benzamide] is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Read More

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5-(2-amino-pyrimidin-4-yl)-1H-pyrrole and 2-(2-amino-pyrimidin-4-yl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one derivatives as new classes of selective and orally available Polo-like kinase 1 inhibitors.

Bioorg Med Chem Lett 2012 Jan 23;22(1):96-101. Epub 2011 Nov 23.

Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, (MI), Italy.

The discovery and characterization of two new chemical classes of potent and selective Polo-like kinase 1 (PLK1) inhibitors is reported. For the most interesting compounds, we discuss the biological activities, crystal structures and preliminary pharmacokinetic parameters. The more advanced compounds inhibit PLK1 in the enzymatic assay at the nM level and exhibit good activity in cell proliferation on A2780 cells. Read More

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January 2012

Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of Polo-like kinase 1 (MLN0905).

J Med Chem 2012 Jan 5;55(1):197-208. Epub 2011 Dec 5.

Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States.

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic-pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. Read More

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January 2012

NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor.

Bioorg Med Chem Lett 2011 May 21;21(10):2969-74. Epub 2011 Mar 21.

Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy.

As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. Read More

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Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors.

J Med Chem 2010 May;53(9):3532-51

Nerviano Medical Sciences Srl, Oncology, Viale Pasteur 10, 20014 Nerviano, (Mi), Italy.

Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0. Read More

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5'-nitro-indirubinoxime induces G2/M cell cycle arrest and apoptosis in human KB oral carcinoma cells.

Cancer Lett 2009 Feb 16;274(1):72-7. Epub 2008 Oct 16.

Department of Biochemistry, Dongguk University College of Oriental Medicine, Gyeongju 780-714, Republic of Korea.

Our previous study demonstrated that the novel indirubin derivative, 5'-nitro-indirubinoxime (5'-NIO), effectively arrested the tumor growth through the inhibition of cell proliferation and the induction of apoptosis. However, the precise molecular mechanisms underlying 5'-NIO-induced antitumor activity remain unclear. Here, we report that 5'-NIO inhibits the proliferation of human KB oral carcinoma cells via the cell cycle arrest in G2/M phase. Read More

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February 2009
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