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  1. 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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  2. Article: Novel beta-lactam derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

    Imbach, Patricia / Lang, Marc / García-Echeverría, Carlos / Guagnano, Vito / Noorani, Maria / Roesel, Johannes / Bitsch, Francis / Rihs, Grety / Furet, Pascal

    Bioorganic & medicinal chemistry letters

    2007  Volume 17, Issue 2, Page(s) 358–362

    Abstract: A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors ... ...

    Abstract A series of beta-lactam derivatives has been designed and synthesized to inhibit the chymotrypsin-like activity of the human 20S proteasome. The most potent compounds of this new structural class of beta-subunit selective 20S proteasome inhibitors exhibit IC50 values in the low-nanomolar range and show good selectivity over the trypsin-like and post-glutamyl-peptide hydrolytic activities of the enzyme.
    MeSH term(s) Chymotrypsin/antagonists & inhibitors ; Crystallography, X-Ray ; Drug Design ; Humans ; Models, Molecular ; Peptides/chemistry ; Proteasome Inhibitors ; Structure-Activity Relationship ; Trypsin Inhibitors/chemical synthesis ; Trypsin Inhibitors/pharmacology ; beta-Lactams/chemical synthesis ; beta-Lactams/pharmacology
    Chemical Substances Peptides ; Proteasome Inhibitors ; Trypsin Inhibitors ; beta-Lactams ; Chymotrypsin (EC 3.4.21.1)
    Language English
    Publishing date 2007-01-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2006.10.047
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3203: Show issues Location:
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  3. Article ; Online: Antileukemic Effects of Novel First- and Second-Generation FLT3 Inhibitors: Structure-Affinity Comparison.

    Weisberg, Ellen / Roesel, Johannes / Furet, Pascal / Bold, Guido / Imbach, Patricia / Flörsheimer, Andreas / Caravatti, Georgio / Jiang, Jingrui / Manley, Paul / Ray, Arghya / Griffin, James D

    Genes & cancer

    2011  Volume 1, Issue 10, Page(s) 1021–1032

    Abstract: Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage ... ...

    Abstract Constitutively activated mutant FLT3 has emerged as a promising target for therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in late-stage clinical trials. However, the identification of PKC412-resistant leukemic blast cells in the bone marrow of AML patients has propelled the development of novel and structurally distinct FLT3 inhibitors that have the potential to override drug resistance and more efficiently prevent disease progression or recurrence. Here, we present the novel first-generation "type II" FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation "type II" derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell cycle inhibition. Cross-resistance between "type I" inhibitors, PKC412 and AAE871, was demonstrated. While cross-resistance was also observed between "type I" and first-generation "type II" FLT3 inhibitors, the high potency of the second-generation "type II" inhibitors was sufficient to potently kill "type I" inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed for the second-generation "type II" inhibitors was observed to be due to an improved interaction with the ATP pocket of FLT3, specifically associated with introduction of a piperazine moiety and placement of an amino group in position 2 of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3 inhibitors characterized by high selectivity and potency toward mutant FLT3 as a molecular target. In addition, presentation of the antileukemic effects of "type II" inhibitors, such as AUZ454 and ATH686, highlights a new class of highly potent FLT3 inhibitors able to override drug resistance that less potent "type I" inhibitors and "type II" first-generation FLT3 inhibitors cannot.
    Language English
    Publishing date 2011-07-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2538519-7
    ISSN 1947-6027 ; 1947-6019
    ISSN (online) 1947-6027
    ISSN 1947-6019
    DOI 10.1177/1947601910396505
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: The small molecule specific EphB4 kinase inhibitor NVP-BHG712 inhibits VEGF driven angiogenesis.

    Martiny-Baron, Georg / Holzer, Philipp / Billy, Eric / Schnell, Christian / Brueggen, Joseph / Ferretti, Mireille / Schmiedeberg, Niko / Wood, Jeanette M / Furet, Pascal / Imbach, Patricia

    Angiogenesis

    2010  Volume 13, Issue 3, Page(s) 259–267

    Abstract: EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults ... ...

    Abstract EphB4 and its cognitive ligand ephrinB2 play an important role in embryonic vessel development and vascular remodeling. In addition, several reports suggest that this receptor ligand pair is also involved in pathologic vessel formation in adults including tumor angiogenesis. Eph/ephrin signaling is a complex phenomena characterized by receptor forward signaling through the tyrosine kinase of the receptor and ephrin reverse signaling through various protein-protein interaction domains and phosphorylation motifs of the ephrin ligands. Therefore, interfering with EphR/ephrin signaling by the means of targeted gene ablation, soluble receptors, dominant negative mutants or antisense molecules often does not allow to discriminate between inhibition of Eph/ephrin forward and reverse signaling. We developed a specific small molecular weight kinase inhibitor of the EphB4 kinase, NVP-BHG712, which inhibits EphB4 kinase activity in the low nanomolar range in cellular assays showed high selectivity for targeting the EphB4 kinase when profiled against other kinases in biochemical as well as in cell based assays. Furthermore, NVP-BHG712 shows excellent pharmacokinetic properties and potently inhibits EphB4 autophosphorylation in tissues after oral administration. In vivo, NVP-BHG712 inhibits VEGF driven vessel formation, while it has only little effects on VEGF receptor (VEGFR) activity in vitro or in cellular assays. The data shown here suggest a close cross talk between the VEGFR and EphR signaling during vessel formation. In addition to its established function in vascular remodeling and endothelial arterio-venous differentiation, EphB4 forward signaling appears to be an important mediator of VEGF induced angiogenesis since inhibition of EphB4 forward signaling is sufficient to inhibit VEGF induced angiogenesis.
    MeSH term(s) Angiogenesis Inhibitors/chemistry ; Angiogenesis Inhibitors/pharmacokinetics ; Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; Animals ; Biological Assay ; Humans ; Lung/drug effects ; Lung/metabolism ; Mice ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/enzymology ; Organ Size/drug effects ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/pharmacokinetics ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use ; Pyrimidines/chemistry ; Pyrimidines/pharmacokinetics ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Receptor, EphB4/antagonists & inhibitors ; Receptor, EphB4/metabolism ; Signal Transduction/drug effects ; Small Molecule Libraries/pharmacology ; Solubility/drug effects ; Vascular Endothelial Growth Factor A/metabolism
    Chemical Substances Angiogenesis Inhibitors ; NVP BH6712 ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; Small Molecule Libraries ; Vascular Endothelial Growth Factor A ; Receptor, EphB4 (EC 2.7.10.1)
    Language English
    Publishing date 2010-08-29
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1484717-6
    ISSN 1573-7209 ; 0969-6970
    ISSN (online) 1573-7209
    ISSN 0969-6970
    DOI 10.1007/s10456-010-9183-z
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5094: Show issues Location:
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  5. Article: Structure-based optimisation of 2-aminobenzylstatine derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome.

    Furet, Pascal / Imbach, Patricia / Fuerst, Peter / Lang, Marc / Noorani, Maria / Zimmermann, Johann / García-Echeverría, Carlos

    Bioorganic & medicinal chemistry letters

    2002  Volume 12, Issue 10, Page(s) 1331–1334

    Abstract: We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of ... ...

    Abstract We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivatives showed good selectivity against the trypsin-like and post-glutamyl-peptide hydrolytic activities of this enzyme.
    MeSH term(s) Benzyl Compounds/chemical synthesis ; Benzyl Compounds/pharmacology ; Chymotrypsin/antagonists & inhibitors ; Cysteine Endopeptidases ; Drug Design ; Humans ; Kinetics ; Models, Molecular ; Molecular Conformation ; Multienzyme Complexes/antagonists & inhibitors ; Protease Inhibitors/chemical synthesis ; Protease Inhibitors/pharmacology ; Proteasome Endopeptidase Complex ; Structure-Activity Relationship
    Chemical Substances Benzyl Compounds ; Multienzyme Complexes ; Protease Inhibitors ; Chymotrypsin (EC 3.4.21.1) ; Cysteine Endopeptidases (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2002-05-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/s0960-894x(02)00178-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  6. Article: Entry into a new class of potent proteasome inhibitors having high antiproliferative activity by structure-based design.

    Furet, Pascal / Imbach, Patricia / Noorani, Maria / Koeppler, Juergen / Laumen, Kurt / Lang, Marc / Guagnano, Vito / Fuerst, Peter / Roesel, Johannes / Zimmermann, Johann / García-Echeverría, Carlos

    Journal of medicinal chemistry

    2004  Volume 47, Issue 20, Page(s) 4810–4813

    Abstract: Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in ... ...

    Abstract Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.
    MeSH term(s) Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Binding Sites ; Cell Division/drug effects ; Cysteine Endopeptidases/chemistry ; Cysteine Endopeptidases/metabolism ; Cysteine Proteinase Inhibitors/chemistry ; Cysteine Proteinase Inhibitors/metabolism ; Cysteine Proteinase Inhibitors/pharmacology ; Drug Screening Assays, Antitumor/methods ; Humans ; Hydrogen Bonding ; Inhibitory Concentration 50 ; Models, Molecular ; Molecular Structure ; Multienzyme Complexes/antagonists & inhibitors ; Multienzyme Complexes/chemistry ; Multienzyme Complexes/metabolism ; Oligopeptides/chemistry ; Oligopeptides/metabolism ; Oligopeptides/pharmacology ; Proteasome Endopeptidase Complex ; Structure-Activity Relationship ; Tumor Cells, Cultured
    Chemical Substances 3-phenoxyphenylalanyl-3,4,5-trimethoxyphenylalanyl-valine 2-hydroxy-4-methoxybenzyl amide ; Antineoplastic Agents ; Cysteine Proteinase Inhibitors ; Multienzyme Complexes ; Oligopeptides ; Cysteine Endopeptidases (EC 3.4.22.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2004-09-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm049660v
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 151: Show issues Location:
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    Zs.MB 1: Show issues

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