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  1. Article ; Online: Design and Synthesis of Pyrrolo[2,3-

    Williamson, Douglas S / Smith, Garrick P / Mikkelsen, Gitte K / Jensen, Thomas / Acheson-Dossang, Pamela / Badolo, Lassina / Bedford, Simon T / Chell, Victoria / Chen, I-Jen / Dokurno, Pawel / Hentzer, Morten / Newland, Samantha / Ray, Stuart C / Shaw, Terry / Surgenor, Allan E / Terry, Lindsey / Wang, Yikang / Christensen, Kenneth V

    Journal of medicinal chemistry

    2021  Volume 64, Issue 14, Page(s) 10312–10332

    Abstract: Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3- ...

    Abstract Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-
    MeSH term(s) Checkpoint Kinase 1/chemistry ; Checkpoint Kinase 1/metabolism ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Design ; HEK293 Cells ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Pyrroles/chemical synthesis ; Pyrroles/chemistry ; Pyrroles/pharmacology ; Structure-Activity Relationship
    Chemical Substances Protein Kinase Inhibitors ; Pyrimidines ; Pyrroles ; Pyrrolo(2,3-d)pyrimidine ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
    Language English
    Publishing date 2021-06-29
    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/acs.jmedchem.1c00720
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).

    Williamson, Douglas S / Smith, Garrick P / Acheson-Dossang, Pamela / Bedford, Simon T / Chell, Victoria / Chen, I-Jen / Daechsel, Justus C A / Daniels, Zoe / David, Laurent / Dokurno, Pawel / Hentzer, Morten / Herzig, Martin C / Hubbard, Roderick E / Moore, Jonathan D / Murray, James B / Newland, Samantha / Ray, Stuart C / Shaw, Terry / Surgenor, Allan E /
    Terry, Lindsey / Thirstrup, Kenneth / Wang, Yikang / Christensen, Kenneth V

    Journal of medicinal chemistry

    2017  Volume 60, Issue 21, Page(s) 8945–8962

    Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in ... ...

    Abstract Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC
    MeSH term(s) Animals ; Brain/metabolism ; Checkpoint Kinase 1 ; Crystallography/methods ; HEK293 Cells ; Humans ; Kidney/metabolism ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Mice ; Mutation ; Parkinson Disease/genetics ; Protein Binding ; Protein Domains ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/therapeutic use
    Chemical Substances Protein Kinase Inhibitors ; Checkpoint Kinase 1 (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
    Language English
    Publishing date 2017-10-27
    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/acs.jmedchem.7b01186
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity.

    Macias, Alba T / Williamson, Douglas S / Allen, Nicola / Borgognoni, Jenifer / Clay, Alexandra / Daniels, Zoe / Dokurno, Pawel / Drysdale, Martin J / Francis, Geraint L / Graham, Christopher J / Howes, Rob / Matassova, Natalia / Murray, James B / Parsons, Rachel / Shaw, Terry / Surgenor, Allan E / Terry, Lindsey / Wang, Yikang / Wood, Mike /
    Massey, Andrew J

    Journal of medicinal chemistry

    2011  Volume 54, Issue 12, Page(s) 4034–4041

    Abstract: 78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and ... ...

    Abstract 78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM and 14 with K(D) = 60 nM. X-ray crystal structures of Grp78 bound to ATP, ADPnP, and adenosine derivative 10 revealed differences in the binding site between Grp78 and homologous proteins.
    MeSH term(s) Adenosine Triphosphatases/antagonists & inhibitors ; Adenosine Triphosphatases/chemistry ; Adenosine Triphosphate/chemistry ; Adenylyl Imidodiphosphate/chemistry ; Binding Sites ; Calorimetry ; Crystallography, X-Ray ; Furans/chemical synthesis ; Furans/chemistry ; HSC70 Heat-Shock Proteins/chemistry ; HSP70 Heat-Shock Proteins/chemistry ; Heat-Shock Proteins/antagonists & inhibitors ; Heat-Shock Proteins/chemistry ; Ligands ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Isoforms/antagonists & inhibitors ; Protein Isoforms/chemistry ; Purines/chemical synthesis ; Purines/chemistry ; Stereoisomerism ; Structure-Activity Relationship ; Surface Plasmon Resonance ; Thermodynamics
    Chemical Substances Furans ; HSC70 Heat-Shock Proteins ; HSP70 Heat-Shock Proteins ; Heat-Shock Proteins ; Ligands ; Protein Isoforms ; Purines ; molecular chaperone GRP78 ; Adenylyl Imidodiphosphate (25612-73-1) ; Adenosine Triphosphate (8L70Q75FXE) ; Adenosine Triphosphatases (EC 3.6.1.-)
    Language English
    Publishing date 2011-06-23
    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/jm101625x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.

    Williamson, Douglas S / Borgognoni, Jenifer / Clay, Alexandra / Daniels, Zoe / Dokurno, Pawel / Drysdale, Martin J / Foloppe, Nicolas / Francis, Geraint L / Graham, Christopher J / Howes, Rob / Macias, Alba T / Murray, James B / Parsons, Rachel / Shaw, Terry / Surgenor, Allan E / Terry, Lindsey / Wang, Yikang / Wood, Mike / Massey, Andrew J

    Journal of medicinal chemistry

    2009  Volume 52, Issue 6, Page(s) 1510–1513

    Abstract: The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were ... ...

    Abstract The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.
    MeSH term(s) Adenosine/chemistry ; Adenosine/pharmacology ; Cell Line, Tumor ; Crystallography, X-Ray ; Drug Design ; Fluorescence Polarization Immunoassay ; HSP70 Heat-Shock Proteins/antagonists & inhibitors ; Humans ; Molecular Structure
    Chemical Substances HSP70 Heat-Shock Proteins ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2009-03-26
    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/jm801627a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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