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  1. Article ; Online: Discovery of WRN inhibitor HRO761 with synthetic lethality in MSI cancers.

    Ferretti, Stephane / Hamon, Jacques / de Kanter, Ruben / Scheufler, Clemens / Andraos-Rey, Rita / Barbe, Stephanie / Bechter, Elisabeth / Blank, Jutta / Bordas, Vincent / Dammassa, Ernesta / Decker, Andrea / Di Nanni, Noemi / Dourdoigne, Marion / Gavioli, Elena / Hattenberger, Marc / Heuser, Alisa / Hemmerlin, Christelle / Hinrichs, Jürgen / Kerr, Grainne /
    Laborde, Laurent / Jaco, Isabel / Núñez, Eloísa Jiménez / Martus, Hans-Joerg / Quadt, Cornelia / Reschke, Markus / Romanet, Vincent / Schaeffer, Fanny / Schoepfer, Joseph / Schrapp, Maxime / Strang, Ross / Voshol, Hans / Wartmann, Markus / Welly, Sarah / Zécri, Frédéric / Hofmann, Francesco / Möbitz, Henrik / Cortés-Cros, Marta

    Nature

    2024  Volume 629, Issue 8011, Page(s) 443–449

    Abstract: The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic ... ...

    Abstract The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens
    MeSH term(s) Animals ; Female ; Humans ; Mice ; Administration, Oral ; Allosteric Regulation/drug effects ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Clinical Trials as Topic ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; DNA Damage/drug effects ; Drug Discovery ; Enzyme Inhibitors/adverse effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Mice, Nude ; Microsatellite Instability ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Neoplasms/metabolism ; Protein Domains ; Reproducibility of Results ; Suppression, Genetic ; Synthetic Lethal Mutations/genetics ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Protein p53/genetics ; Werner Syndrome Helicase/antagonists & inhibitors ; Werner Syndrome Helicase/genetics ; Werner Syndrome Helicase/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Tumor Suppressor Protein p53 ; Werner Syndrome Helicase (EC 3.6.4.12) ; WRN protein, human (EC 3.6.4.12)
    Language English
    Publishing date 2024-04-24
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-024-07350-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 26: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (1.OG)
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    Zs.MG 9: Show issues
    Zs.MO 244: Show issues

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  2. Article ; Online: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

    Schröder, Martin / Renatus, Martin / Liang, Xiaoyou / Meili, Fabian / Zoller, Thomas / Ferrand, Sandrine / Gauter, Francois / Li, Xiaoyan / Sigoillot, Frederic / Gleim, Scott / Stachyra, Therese-Marie / Thomas, Jason R / Begue, Damien / Khoshouei, Maryam / Lefeuvre, Peggy / Andraos-Rey, Rita / Chung, BoYee / Ma, Renate / Pinch, Benika /
    Hofmann, Andreas / Schirle, Markus / Schmiedeberg, Niko / Imbach, Patricia / Gorses, Delphine / Calkins, Keith / Bauer-Probst, Beatrice / Maschlej, Magdalena / Niederst, Matt / Maher, Rob / Henault, Martin / Alford, John / Ahrne, Erik / Tordella, Luca / Hollingworth, Greg / Thomä, Nicolas H / Vulpetti, Anna / Radimerski, Thomas / Holzer, Philipp / Carbonneau, Seth / Thoma, Claudio R

    Nature communications

    2024  Volume 15, Issue 1, Page(s) 275

    Abstract: Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So ... ...

    Abstract Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4
    MeSH term(s) Carrier Proteins/metabolism ; Proteolysis ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Proteolysis Targeting Chimera
    Chemical Substances Carrier Proteins ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteolysis Targeting Chimera
    Language English
    Publishing date 2024-01-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-44237-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A proteomic study of myeloproliferative neoplasms using reverse-phase protein arrays.

    Tognon, Raquel / Almeida-E-Silva, Danillo C / Andraos-Rey, Rita / Ristov, Mitko / Ambrósio, Luciana / de Almeida, Felipe Campos / de Souza Nunes, Natália / Xisto Souto, Elizabeth / de Lourdes Perobelli, Leila / Simões, Belinda Pinto / Alexander Guthy, Daniel / Radimerski, Thomas / Attié de Castro, Fabíola

    Leukemia & lymphoma

    2020  Volume 61, Issue 13, Page(s) 3052–3065

    Abstract: Myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis constitute a group of haematological diseases. The comprehensive assessment of signaling pathway activation in blood cells may aid the ... ...

    Abstract Myeloproliferative neoplasms polycythemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis constitute a group of haematological diseases. The comprehensive assessment of signaling pathway activation in blood cells may aid the understanding of MPN pathophysiology. Thus, levels of post-translational protein modifications and total protein expression were determined in MPN patients and control leukocytes by using reverse-phase protein arrays (RPPA). Compared to control samples, p-SRC, p-CTNNB1, c-MYC, MCL-1, p-MDM2, BAX and CCNB1 showed higher expression in PV samples than controls. P-JAK2/JAK2 and pro-apoptotic BIM showed differential expression between
    MeSH term(s) Humans ; Janus Kinase 2/genetics ; Mutation ; Myeloproliferative Disorders/diagnosis ; Myeloproliferative Disorders/genetics ; Neoplasms ; Phosphatidylinositol 3-Kinases ; Protein Array Analysis ; Proteomics
    Chemical Substances Janus Kinase 2 (EC 2.7.10.2)
    Language English
    Publishing date 2020-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1042374-6
    ISSN 1029-2403 ; 1042-8194
    ISSN (online) 1029-2403
    ISSN 1042-8194
    DOI 10.1080/10428194.2020.1805110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2997: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
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  4. Article ; Online: A conditional inducible JAK2V617F transgenic mouse model reveals myeloproliferative disease that is reversible upon switching off transgene expression.

    Chapeau, Emilie A / Mandon, Emeline / Gill, Jason / Romanet, Vincent / Ebel, Nicolas / Powajbo, Violetta / Andraos-Rey, Rita / Qian, Zhiyan / Kininis, Miltos / Zumstein-Mecker, Sabine / Ito, Moriko / Hynes, Nancy E / Tiedt, Ralph / Hofmann, Francesco / Eshkind, Leonid / Bockamp, Ernesto / Kinzel, Bernd / Mueller, Matthias / Murakami, Masato /
    Baffert, Fabienne / Radimerski, Thomas

    PloS one

    2019  Volume 14, Issue 10, Page(s) e0221635

    Abstract: Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration ... ...

    Abstract Aberrant activation of the JAK/STAT pathway is thought to be the critical event in the pathogenesis of the chronic myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia and primary myelofibrosis. The most frequent genetic alteration in these pathologies is the activating JAK2V617F mutation, and expression of the mutant gene in mouse models was shown to cause a phenotype resembling the human diseases. Given the body of genetic evidence, it has come as a sobering finding that JAK inhibitor therapy only modestly suppresses the JAK2V617F allele burden, despite showing clear benefits in terms of reducing splenomegaly and constitutional symptoms in patients. To gain a better understanding if JAK2V617F is required for maintenance of myeloproliferative disease once it has evolved, we generated a conditional inducible transgenic JAK2V617F mouse model using the SCL-tTA-2S tet-off system. Our model corroborates that expression of JAK2V617F in hematopoietic stem and progenitor cells recapitulates key hallmarks of human myeloproliferative neoplasms, and exhibits gender differences in disease manifestation. The disease was found to be transplantable, and importantly, reversible when transgenic JAK2V617F expression was switched off. Our results indicate that mutant JAK2V617F-specific inhibitors should result in profound disease modification by disabling the myeloproliferative clone bearing mutant JAK2.
    MeSH term(s) Amino Acid Substitution ; Animals ; Disease Models, Animal ; Gene Expression Regulation ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Humans ; Janus Kinase 2/biosynthesis ; Janus Kinase 2/genetics ; Mice ; Mice, Transgenic ; Mutation, Missense ; Myeloproliferative Disorders/genetics ; Myeloproliferative Disorders/metabolism ; Myeloproliferative Disorders/pathology ; Transgenes
    Chemical Substances JAK2 protein, human (EC 2.7.10.2) ; Jak2 protein, mouse (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2)
    Language English
    Publishing date 2019-10-10
    Publishing country United States
    Document type Journal Article
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0221635
    Database MEDical Literature Analysis and Retrieval System OnLINE

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