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  1. Article ; Online: Discovery of Small Molecule Interleukin 17A Inhibitors with Novel Binding Mode and Stoichiometry: Optimization of DNA-Encoded Chemical Library Hits to In Vivo Active Compounds.

    Ramos, Ashley L / Goedken, Eric R / Frank, Kristine E / Argiriadi, Maria A / Bazzaz, Sana / Bian, Zhiguo / Brown, Jesse T C / Centrella, Paolo A / Chen, Hui-Ju / Disch, Jeremy S / Donner, Pamela L / Duignan, David B / Gikunju, Diana / Greszler, Stephen N / Guié, Marie-Aude / Habeshian, Sevan / Hartl, Hajnalka E / Hein, Christopher D / Hutchins, Charles W /
    Jetson, Rachael / Keefe, Anthony D / Khan, Hasan / Li, Huan-Qiu / Olszewski, Allison / Ortiz Cardona, Benjamin J / Osuma, Augustine / Panchal, Sanjay C / Phelan, Ryan / Qiu, Wei / Shotwell, J Brad / Shrestha, Anurupa / Srikumaran, Myron / Su, Zhi / Sun, Chaohong / Upadhyay, Anup K / Wood, Michael D / Wu, Haihong / Zhang, Ruijie / Zhang, Ying / Zhao, Gang / Zhu, Haizhong / Webster, Matthew P

    Journal of medicinal chemistry

    2024  Volume 67, Issue 8, Page(s) 6456–6494

    Abstract: Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule ...

    Abstract Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.
    MeSH term(s) Interleukin-17/metabolism ; Interleukin-17/antagonists & inhibitors ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; DNA/metabolism ; DNA/chemistry ; Humans ; Drug Discovery ; Animals ; Structure-Activity Relationship ; Protein Binding ; Mice
    Chemical Substances Interleukin-17 ; Small Molecule Libraries ; DNA (9007-49-2) ; IL17A protein, human
    Language English
    Publishing date 2024-04-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.3c02397
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 151: Show issues Location:
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  2. Article ; Online: Tricyclic covalent inhibitors selectively target Jak3 through an active site thiol.

    Goedken, Eric R / Argiriadi, Maria A / Banach, David L / Fiamengo, Bryan A / Foley, Sage E / Frank, Kristine E / George, Jonathan S / Harris, Christopher M / Hobson, Adrian D / Ihle, David C / Marcotte, Douglas / Merta, Philip J / Michalak, Mark E / Murdock, Sara E / Tomlinson, Medha J / Voss, Jeffrey W

    The Journal of biological chemistry

    2014  Volume 290, Issue 8, Page(s) 4573–4589

    Abstract: The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, ... ...

    Abstract The action of Janus kinases (JAKs) is required for multiple cytokine signaling pathways, and as such, JAK inhibitors hold promise for treatment of autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, due to high similarity in the active sites of the four members (Jak1, Jak2, Jak3, and Tyk2), developing selective inhibitors within this family is challenging. We have designed and characterized substituted, tricyclic Jak3 inhibitors that selectively avoid inhibition of the other JAKs. This is accomplished through a covalent interaction between an inhibitor containing a terminal electrophile and an active site cysteine (Cys-909). We found that these ATP competitive compounds are irreversible inhibitors of Jak3 enzyme activity in vitro. They possess high selectivity against other kinases and can potently (IC50 < 100 nm) inhibit Jak3 activity in cell-based assays. These results suggest irreversible inhibitors of this class may be useful selective agents, both as tools to probe Jak3 biology and potentially as therapies for autoimmune diseases.
    MeSH term(s) Adenosine Triphosphate/analogs & derivatives ; Adenosine Triphosphate/chemistry ; Adenosine Triphosphate/pharmacology ; Autoimmune Diseases/drug therapy ; Autoimmune Diseases/enzymology ; Autoimmune Diseases/genetics ; Catalytic Domain ; Cell Line ; Humans ; Janus Kinase 3/antagonists & inhibitors ; Janus Kinase 3/chemistry ; Janus Kinase 3/genetics ; Janus Kinase 3/metabolism ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology
    Chemical Substances Protein Kinase Inhibitors ; Adenosine Triphosphate (8L70Q75FXE) ; JAK3 protein, human (EC 2.7.10.2) ; Janus Kinase 3 (EC 2.7.10.2)
    Language English
    Publishing date 2014-12-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M114.595181
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Structure activity optimization of 6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazines as Jak1 kinase inhibitors.

    Friedman, Michael / Frank, Kristine E / Aguirre, Ana / Argiriadi, Maria A / Davis, Heather / Edmunds, Jeremy J / George, Dawn M / George, Jonathan S / Goedken, Eric / Fiamengo, Bryan / Hyland, Deborah / Li, Bin / Murtaza, Anwar / Morytko, Michael / Somal, Gagandeep / Stewart, Kent / Tarcsa, Edit / Van Epps, Stacy / Voss, Jeffrey /
    Wang, Lu / Woller, Kevin / Wishart, Neil

    Bioorganic & medicinal chemistry letters

    2015  Volume 25, Issue 20, Page(s) 4399–4404

    Abstract: Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally ... ...

    Abstract Previous work investigating tricyclic pyrrolopyrazines as kinase cores led to the discovery that 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (12) had Jak inhibitory activity. Herein we describe our initial efforts to develop orally bioavailable analogs of 12 with improved selectivity of Jak1 over Jak2.
    MeSH term(s) Animals ; Cell Line ; Dose-Response Relationship, Drug ; Humans ; Janus Kinase 1/antagonists & inhibitors ; Janus Kinase 1/metabolism ; Male ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrazines/chemical synthesis ; Pyrazines/chemistry ; Pyrazines/pharmacology ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Triazoles/chemical synthesis ; Triazoles/chemistry ; Triazoles/pharmacology
    Chemical Substances 6H-pyrrolo(2,3-e)(1,2,4)triazolo(4,3-a)pyrazine ; Protein Kinase Inhibitors ; Pyrazines ; Triazoles ; JAK1 protein, human (EC 2.7.10.2) ; Janus Kinase 1 (EC 2.7.10.2)
    Language English
    Publishing date 2015-10-15
    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.2015.09.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: 2,4-Diaminopyrimidine MK2 inhibitors. Part II: Structure-based inhibitor optimization.

    Harris, Christopher M / Ericsson, Anna M / Argiriadi, Maria A / Barberis, Claude / Borhani, David W / Burchat, Andrew / Calderwood, David J / Cunha, George A / Dixon, Richard W / Frank, Kristine E / Johnson, Eric F / Kamens, Joanne / Kwak, Silvia / Li, Biqin / Mullen, Kelly D / Perron, Denise C / Wang, Lu / Wishart, Neil / Wu, Xiaoyun /
    Zhang, Xiaolei / Zmetra, Tami R / Talanian, Robert V

    Bioorganic & medicinal chemistry letters

    2010  Volume 20, Issue 1, Page(s) 334–337

    Abstract: We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and ... ...

    Abstract We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.
    MeSH term(s) Administration, Oral ; Animals ; Anti-Inflammatory Agents/chemical synthesis ; Anti-Inflammatory Agents/chemistry ; Anti-Inflammatory Agents/pharmacokinetics ; Binding Sites ; Computer Simulation ; Crystallography, X-Ray ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/metabolism ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/metabolism ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Pyrimidines/pharmacokinetics ; Rats ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Anti-Inflammatory Agents ; Intracellular Signaling Peptides and Proteins ; Protein Kinase Inhibitors ; Pyrimidines ; Tumor Necrosis Factor-alpha ; 2,4-diaminopyrimidine (156-81-0) ; MAP-kinase-activated kinase 2 (EC 2.7.1.-) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2010-01-01
    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.2009.10.103
    Database MEDical Literature Analysis and Retrieval System OnLINE

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