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Article ; Online: PARP inhibitors in cancer therapy: an update.

Papeo, Gianluca / Casale, Elena / Montagnoli, Alessia / Cirla, Alessandra

2013 Volume 23, Issue 4, Page(s) 503–514

Abstract: Introduction: Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently being evaluated as potential anticancer medicines at both preclinical and clinical levels. They have the peculiarity to increase the efficacy of DNA- ... ...

Abstract	Introduction: Inhibitors of the poly(ADP-ribose) polymerases (PARPs) family of proteins are currently being evaluated as potential anticancer medicines at both preclinical and clinical levels. They have the peculiarity to increase the efficacy of DNA-damaging agents and to selectively target tumor cells with specific DNA repair defects. This later development of these drugs should make it possible, in principle, to selectively target neoplastic vs healthy cells, thus realizing the Ehrlich's magic bullet concept of a personalized and tailored cure of diseases. Areas covered: This review is designed to provide the readers with a brief summary and an update on PARP inhibitors in the oncology field, by covering the recent patent literature (2010 - 2012: and Questel Intellectual Property Portal [QPat] database search). Expert opinion: Presently, along with a number of preclinical candidates, there are eight PARP inhibitors in the clinic as either single agents or in combination with various chemotherapy and radiotherapy regimens. The tremendous efforts underneath those results testify the high interest on the target. The investigation and understanding of the cross-reactivity among members of the PARPs family as well as a deeper knowledge of their biological functions may lead to a more profound characterization of the PARP inhibitor's profile. This, in turn, will cast additional light on this exciting approach in treating cancer.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug Design ; Drug and Narcotic Control ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Molecular Structure ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/pathology ; Patents as Topic ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/metabolism ; Signal Transduction/drug effects ; Structure-Activity Relationship
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2013-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1517/13543776.2013.768615
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Article: Targeting cell division cycle 7 kinase: a new approach for cancer therapy.

Montagnoli, Alessia / Moll, Jürgen / Colotta, Francesco

Clinical cancer research : an official journal of the American Association for Cancer Research

2010 Volume 16, Issue 18, Page(s) 4503–4508

Abstract: The cell division cycle 7 (Cdc7) is a serine-threonine kinase, originally discovered in budding yeast, required to initiate DNA replication. Human Cdc7 phosphorylates the minichromosome maintenance protein 2 (Mcm2), a component of the DNA replicative ... ...

Abstract	The cell division cycle 7 (Cdc7) is a serine-threonine kinase, originally discovered in budding yeast, required to initiate DNA replication. Human Cdc7 phosphorylates the minichromosome maintenance protein 2 (Mcm2), a component of the DNA replicative helicase needed for genome duplication. Inhibition of Cdc7 in cancer cells impairs progression through S phase, inducing a p53-independent apoptotic cell death, whereas in normal cells, it does not affect cell viability. Small molecule compounds able to interfere with Cdc7 activity have been identified and shown to be effective in controlling tumor growth in animal models. Two Cdc7 inhibitors are currently in phase I clinical development. Inhibition of Cdc7 kinase activity in cancer cells restricts DNA replication and induces apoptotic cell death by an unprecedented molecular mechanism of action.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Apoptosis/genetics ; Apoptosis/physiology ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/physiology ; Clinical Trials, Phase I as Topic ; DNA Replication/drug effects ; DNA Replication/genetics ; Humans ; Models, Biological ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/trends ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/physiology ; Therapies, Investigational/methods ; Therapies, Investigational/trends
Chemical Substances	Antineoplastic Agents ; Cell Cycle Proteins ; Protein Kinase Inhibitors ; CDC7 protein, human (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2010-09-15
Publishing country	United States
Document type	Evaluation Studies ; Journal Article ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-10-0185
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Article: Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.

Papeo, Gianluca / Orsini, Paolo / Avanzi, Nilla R / Borghi, Daniela / Casale, Elena / Ciomei, Marina / Cirla, Alessandra / Desperati, Viviana / Donati, Daniele / Felder, Eduard R / Galvani, Arturo / Guanci, Marco / Isacchi, Antonella / Posteri, Helena / Rainoldi, Sonia / Riccardi-Sirtori, Federico / Scolaro, Alessandra / Montagnoli, Alessia

ACS medicinal chemistry letters

2019 Volume 10, Issue 4, Page(s) 534–538

Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs ... ...

Abstract	Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD
Language	English
Publishing date	2019-03-13
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.8b00569
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Article ; Online: Poly(ADP-ribose) polymerase inhibition in cancer therapy: are we close to maturity?

Papeo, Gianluca / Forte, Barbara / Orsini, Paolo / Perrera, Claudia / Posteri, Helena / Scolaro, Alessandra / Montagnoli, Alessia

Expert opinion on therapeutic patents

2009 Volume 19, Issue 10, Page(s) 1377–1400

Abstract: Background: During the last few years an increasing number of poly(ADP-ribose) polymerase (PARP) inhibitors have been appearing in the context of cancer therapy. This is mainly due to a better knowledge of the best-characterized member of the PARP ... ...

Abstract	Background: During the last few years an increasing number of poly(ADP-ribose) polymerase (PARP) inhibitors have been appearing in the context of cancer therapy. This is mainly due to a better knowledge of the best-characterized member of the PARP family of enzymes, PARP-1, further reinforced by the recognition of the clinical benefits arising from its inhibition. Objective/method: The aim of this review is to give the reader an update on PARP inhibition in cancer therapy, by covering both the scientific (SciFinder) search) and the patent literature (Chemical Abstract/Derwent search) published recently (2005-2008). Conclusions: More patient-compliant orally available PARP-1 inhibitor clinical candidates, along with their possible use as single agents in specific, molecularly defined cancer indications, increase the expectations for this therapeutic approach. The growing understanding of the biological role of other PARPs, such as Tankyrase 1, may be of interest as new potential targets. Besides the classical NAD-mimicking pharmacophore, additional compounds, which either do not resemble nicotinamide or exploit different binding sites, are emerging.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Binding Sites ; Drug Design ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/therapeutic use ; Humans ; Molecular Structure ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Patents as Topic ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases/chemistry ; Poly(ADP-ribose) Polymerases/metabolism ; Protein Conformation ; Structure-Activity Relationship ; Treatment Outcome
Chemical Substances	Antineoplastic Agents ; Enzyme Inhibitors ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2009-10
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1186201-4
ISSN	1744-7674 ; 0962-2594 ; 1354-3776
ISSN (online)	1744-7674
ISSN	0962-2594 ; 1354-3776
DOI	10.1517/13543770903215883
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Article: Cdc7 Is an Active Kinase in Human Cancer Cells Undergoing Replication Stress

Tenca, Pierluigi / Brotherton, Deborah / Montagnoli, Alessia / Rainoldi, Sonia / Albanese, Clara / Santocanale, Corrado

Journal of biological chemistry. 2007 Jan. 5, v. 282, no. 1

2007

Abstract: Cdc7 kinase promotes and regulates DNA replication in eukaryotic organisms. Multiple mechanisms modulating kinase activity in response to DNA replication stress have been reported, supporting the opposing notions that Cdc7 either plays an active role ... ...

Abstract	Cdc7 kinase promotes and regulates DNA replication in eukaryotic organisms. Multiple mechanisms modulating kinase activity in response to DNA replication stress have been reported, supporting the opposing notions that Cdc7 either plays an active role under these conditions or, conversely, is a final target inactivated by a checkpoint response. We have developed new immnunological reagents to study the properties of human Cdc7 kinase in cells challenged with the ribonucleotide reductase inhibitor hydroxyurea or with the DNA topoisomerase II inhibitor etoposide. We show that Cdc7·Dbf4 and Cdc7·Drf1 complexes are stable and active in multiple cell lines upon drug treatment, with Cdc7·Dbf4 accumulating on chromatin-enriched fractions. Cdc7 depletion by small interfering RNA in hydroxyurea and etoposide impairs hyper-phosphorylation of Mcm2 at specific Cdc7-dependent phosphorylation sites and drug-induced hyper-phosphorylation of chromatin-bound Mcm4. Furthermore, sustained inhibition of Cdc7 in the presence of these drugs increases cell death supporting the notion that the Cdc7 kinase plays a role in maintaining cell viability during replication stress.
Language	English
Dates of publication	2007-0105
Size	p. 208-215.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Afatinib Is a New Therapeutic Approach in Chordoma with a Unique Ability to Target EGFR and Brachyury.

Magnaghi, Paola / Salom, Barbara / Cozzi, Liviana / Amboldi, Nadia / Ballinari, Dario / Tamborini, Elena / Gasparri, Fabio / Montagnoli, Alessia / Raddrizzani, Laura / Somaschini, Alessio / Bosotti, Roberta / Orrenius, Christian / Bozzi, Fabio / Pilotti, Silvana / Galvani, Arturo / Sommer, Josh / Stacchiotti, Silvia / Isacchi, Antonella

Molecular cancer therapeutics

2017 Volume 17, Issue 3, Page(s) 603–613

Abstract: Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II ... ...

Abstract	Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRβ, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRβ inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC
MeSH term(s)	Afatinib/therapeutic use ; Animals ; Bone Neoplasms/drug therapy ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chordoma/drug therapy ; Chordoma/genetics ; Chordoma/metabolism ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Fetal Proteins/antagonists & inhibitors ; Fetal Proteins/genetics ; Fetal Proteins/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice, Nude ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/therapeutic use ; T-Box Domain Proteins/antagonists & inhibitors ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism ; Tumor Burden/drug effects ; Tumor Burden/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Fetal Proteins ; Protein Kinase Inhibitors ; T-Box Domain Proteins ; Afatinib (41UD74L59M) ; ErbB Receptors (EC 2.7.10.1) ; Brachyury protein (EQ43SC3GDB)
Language	English
Publishing date	2017-12-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-17-0324
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Article ; Online: Mechanisms of action of a dual Cdc7/Cdk9 kinase inhibitor against quiescent and proliferating CLL cells.

Natoni, Alessandro / Murillo, Laura S / Kliszczak, Anna E / Catherwood, Mark A / Montagnoli, Alessia / Samali, Afshin / O'Dwyer, Michael / Santocanale, Corrado

Molecular cancer therapeutics

2011 Volume 10, Issue 9, Page(s) 1624–1634

Abstract: In chronic lymphocytic leukemia (CLL) the proliferation rate and resistance to drug-induced apoptosis are recognized as important factors in the outcome of treatment. In this study, we assess the activity and the mechanism of action of the prototype cell ...

Abstract	In chronic lymphocytic leukemia (CLL) the proliferation rate and resistance to drug-induced apoptosis are recognized as important factors in the outcome of treatment. In this study, we assess the activity and the mechanism of action of the prototype cell division cycle kinase 7 (Cdc7) inhibitor, PHA-767491, which inhibits the initiation of DNA replication but also has cyclin-dependent kinase 9 (Cdk9) inhibitory activity. We have studied the effects of this dual Cdc7/Cdk9 inhibitor in both quiescent CLL cells and CLL cells that have been induced to proliferate using a cellular coculture system that mimics the lymph node microenvironment. We find that this compound, originally developed as a DNA replication inhibitor, is particularly active in promoting mitochondrial dependent apoptosis in quiescent CLL cells purified from peripheral blood of patients regardless of recognized risk factors. In this setting, apoptosis is preceded by a decrease in the levels of Mcl-1 protein and transcript possibly due to inhibition of Cdk9. Following stimulation by CD154 and interleukin-4, CLL cells become highly chemoresistant, reenter into the cell cycle, reexpress Cdc7 kinase, a key molecular switch for the initiation of DNA replication, replicate their DNA, and undergo cell division. In this context, treatment with PHA-767491 abolished DNA synthesis by inhibiting Cdc7 but is less effective in triggering cell death, although Mcl-1 protein is no longer detectable. Thus, dual Cdc7/Cdk9 inhibition has the potential to target both the quiescent and actively proliferating CLL populations through two distinct mechanisms and may be a new therapeutic strategy in CLL.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; CD40 Ligand/metabolism ; Caspases/metabolism ; Cell Cycle/drug effects ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cells, Cultured ; Cyclin-Dependent Kinase 9/antagonists & inhibitors ; Cyclin-Dependent Kinase 9/metabolism ; DNA Replication/drug effects ; Gene Expression Regulation, Leukemic/drug effects ; Humans ; Interleukin-4/pharmacology ; Leukemia, Lymphocytic, Chronic, B-Cell/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell/metabolism ; Mice ; Myeloid Cell Leukemia Sequence 1 Protein ; NIH 3T3 Cells ; Phosphorylation/drug effects ; Piperidones/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrroles/pharmacology ; RNA Polymerase II/metabolism ; Signal Transduction/drug effects
Chemical Substances	Antineoplastic Agents ; Cell Cycle Proteins ; Mcl1 protein, mouse ; Myeloid Cell Leukemia Sequence 1 Protein ; PHA 767491 ; Piperidones ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-bcl-2 ; Pyrroles ; CD40 Ligand (147205-72-9) ; Interleukin-4 (207137-56-2) ; CDC7 protein, human (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Cyclin-Dependent Kinase 9 (EC 2.7.11.22) ; RNA Polymerase II (EC 2.7.7.-) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2011-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-10-1119
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Article ; Online: Insights into PARP Inhibitors' Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays.

Papeo, Gianluca / Avanzi, Nilla / Bettoni, Serena / Leone, Antonella / Paolucci, Mauro / Perego, Rita / Quartieri, Francesca / Riccardi-Sirtori, Federico / Thieffine, Sandrine / Montagnoli, Alessia / Lupi, Rosita

Journal of biomolecular screening

2014 Volume 19, Issue 8, Page(s) 1212–1219

Abstract: PARP inhibitors are an exciting new class of antineoplastic drugs that have been proven to be efficacious as single agents in cancer settings with inherent DNA repair defects, as well as in combination with DNA-damaging chemotherapeutics. Currently, they ...

Abstract	PARP inhibitors are an exciting new class of antineoplastic drugs that have been proven to be efficacious as single agents in cancer settings with inherent DNA repair defects, as well as in combination with DNA-damaging chemotherapeutics. Currently, they are designed to target the catalytic domain of PARP-1, the most studied member of the family, with a key role in the DNA-damage repair process. Because PARP inhibitors are substrate (NAD(+)) competitors, there is a need for a deeper understanding of their cross-reactivity. This is particularly relevant for PARP-2, the PARP-1 closest homologue, for which an embryonic lethal phenotype has been observed in double knockout mice. In this study, we describe the development and validation of binding assays based on fluorescence polarization (FP) and surface plasmon resonance (SPR) techniques. PARP-1, PARP-2, PARP-3, and TNKS-1 FP displacement assays are set up by employing ad hoc synthesized probes. These assays are suitable for high-throughput screening (HTS) and selectivity profiling, thus allowing the identification of NAD(+)binding site selective inhibitors. The PARP-1 and PARP-2 complementary SPR binding assays confirm displacement data and the in-depth inhibitor characterization. Moreover, these formats have the potential to be broadly applicable to other members of the PARP family.
MeSH term(s)	Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Fluorescence Polarization/methods ; High-Throughput Screening Assays/methods ; Humans ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerases/genetics ; Poly(ADP-ribose) Polymerases/metabolism ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Reproducibility of Results ; Surface Plasmon Resonance/methods ; Tankyrases/genetics ; Tankyrases/metabolism
Chemical Substances	Cell Cycle Proteins ; Poly(ADP-ribose) Polymerase Inhibitors ; Recombinant Proteins ; PARP1 protein, human (EC 2.4.2.30) ; PARP2 protein, human (EC 2.4.2.30) ; PARP3 protein, human (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Tankyrases (EC 2.4.2.30) ; TNKS protein, human (EC 2.4.4.30)
Language	English
Publishing date	2014-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1433680-7
ISSN	1552-454X ; 1087-0571
ISSN (online)	1552-454X
ISSN	1087-0571
DOI	10.1177/1087057114538319
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Article: Cdc7 is an active kinase in human cancer cells undergoing replication stress.

Tenca, Pierluigi / Brotherton, Deborah / Montagnoli, Alessia / Rainoldi, Sonia / Albanese, Clara / Santocanale, Corrado

The Journal of biological chemistry

2006 Volume 282, Issue 1, Page(s) 208–215

Abstract	Cdc7 kinase promotes and regulates DNA replication in eukaryotic organisms. Multiple mechanisms modulating kinase activity in response to DNA replication stress have been reported, supporting the opposing notions that Cdc7 either plays an active role under these conditions or, conversely, is a final target inactivated by a checkpoint response. We have developed new immnunological reagents to study the properties of human Cdc7 kinase in cells challenged with the ribonucleotide reductase inhibitor hydroxyurea or with the DNA topoisomerase II inhibitor etoposide. We show that Cdc7.Dbf4 and Cdc7.Drf1 complexes are stable and active in multiple cell lines upon drug treatment, with Cdc7.Dbf4 accumulating on chromatin-enriched fractions. Cdc7 depletion by small interfering RNA in hydroxyurea and etoposide impairs hyper-phosphorylation of Mcm2 at specific Cdc7-dependent phosphorylation sites and drug-induced hyper-phosphorylation of chromatin-bound Mcm4. Furthermore, sustained inhibition of Cdc7 in the presence of these drugs increases cell death supporting the notion that the Cdc7 kinase plays a role in maintaining cell viability during replication stress.
MeSH term(s)	Apoptosis ; Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/physiology ; Cell Survival ; Chromatin/chemistry ; DNA/chemistry ; Etoposide/chemistry ; Etoposide/pharmacology ; HeLa Cells ; Humans ; Hydroxyurea/chemistry ; Hydroxyurea/pharmacology ; Minichromosome Maintenance Complex Component 2 ; Nuclear Proteins/physiology ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Ribonucleotide Reductases/antagonists & inhibitors
Chemical Substances	Cell Cycle Proteins ; Chromatin ; Nuclear Proteins ; RNA, Small Interfering ; Etoposide (6PLQ3CP4P3) ; DNA (9007-49-2) ; Ribonucleotide Reductases (EC 1.17.4.-) ; CDC7 protein, human (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; MCM2 protein, human (EC 3.6.4.12) ; Minichromosome Maintenance Complex Component 2 (EC 3.6.4.12) ; Hydroxyurea (X6Q56QN5QC)
Language	English
Publishing date	2006-10-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M604457200
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Article: Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models.

Natoni, Alessandro / Coyne, Mark R E / Jacobsen, Alan / Rainey, Michael D / O'Brien, Gemma / Healy, Sandra / Montagnoli, Alessia / Moll, Jürgen / O'Dwyer, Michael / Santocanale, Corrado

Cancers

2013 Volume 5, Issue 3, Page(s) 901–918

Abstract: Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are ... ...

Abstract	Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma.
Language	English
Publishing date	2013-07-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers5030901
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