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  1. Article ; Online: Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3.

    Galal, Kareem A / Krämer, Andreas / Strickland, Benjamin G / Smith, Jeffery L / Dickmander, Rebekah J / Moorman, Nathaniel J / Willson, Timothy M

    Bioorganic & medicinal chemistry letters

    2024  Volume 99, Page(s) 129617

    Abstract: We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4'-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, ...

    Abstract We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4'-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, modifications of the 6-isopropylaminoindazole substituent were explored to improve selectivity over PIM3 while maintaining potent CSNK2A inhibition. The 6-isopropoxyindole analogue 6c was identified as a nanomolar CSNK2A inhibitor with 30-fold selectivity over PIM3 in cells. Replacement of the 6-isopropoxyindole by isosteric ortho-methoxy anilines, such as 7c, generated analogues with selectivity for CSNK2A over PIM3 and improved the kinome-wide selectivity. The optimized 2,6-disubstituted pyrazines showed inhibition of viral replication consistent with their CSNK2A activity.
    MeSH term(s) Structure-Activity Relationship ; Benzoates ; Pyrazines/pharmacology ; Antiviral Agents/pharmacology
    Chemical Substances Benzoates ; Pyrazines ; Antiviral Agents
    Language English
    Publishing date 2024-01-08
    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.2024.129617
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3203: Show issues Location:
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  2. Article: Synthesis of 5-Benzylamino and 5-Alkylamino-Substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity.

    Asressu, Kesatebrhan Haile / Smith, Jeffery L / Dickmander, Rebekah J / Moorman, Nathaniel J / Wellnitz, James / Popov, Konstantin I / Axtman, Alison D / Willson, Timothy M

    Pharmaceuticals (Basel, Switzerland)

    2024  Volume 17, Issue 3

    Abstract: A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous ... ...

    Abstract A series of 5-benzylamine-substituted pyrimido[4,5-c]quinoline derivatives of the CSNK2A chemical probe SGC-CK2-2 were synthesized with the goal of improving kinase inhibitor cellular potency and antiviral phenotypic activity while maintaining aqueous solubility. Among the range of analogs, those bearing electron-withdrawing (
    Language English
    Publishing date 2024-02-27
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph17030306
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Illuminating function of the understudied druggable kinome.

    Gomez, Shawn M / Axtman, Alison D / Willson, Timothy M / Major, Michael B / Townsend, Reid R / Sorger, Peter K / Johnson, Gary L

    Drug discovery today

    2024  Volume 29, Issue 3, Page(s) 103881

    Abstract: The human kinome, with more than 500 proteins, is crucial for cell signaling and disease. Yet, about one-third of kinases lack in-depth study. The Data and Resource Generating Center for Understudied Kinases has developed multiple resources to address ... ...

    Abstract The human kinome, with more than 500 proteins, is crucial for cell signaling and disease. Yet, about one-third of kinases lack in-depth study. The Data and Resource Generating Center for Understudied Kinases has developed multiple resources to address this challenge including creation of a heavy amino acid peptide library for parallel reaction monitoring and quantitation of protein kinase expression, use of understudied kinases tagged with a miniTurbo-biotin ligase to determine interaction networks by proximity-dependent protein biotinylation, NanoBRET probe development for screening chemical tool target specificity in live cells, characterization of small molecule chemical tools inhibiting understudied kinases, and computational tools for defining kinome architecture. These resources are available through the Dark Kinase Knowledgebase, supporting further research into these understudied protein kinases.
    MeSH term(s) Humans ; Protein Kinases/metabolism ; Proteins ; Proteomics
    Chemical Substances Protein Kinases (EC 2.7.-) ; Proteins
    Language English
    Publishing date 2024-01-11
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1324988-5
    ISSN 1878-5832 ; 1359-6446
    ISSN (online) 1878-5832
    ISSN 1359-6446
    DOI 10.1016/j.drudis.2024.103881
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4725: Show issues Location:
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  4. Article ; Online: Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells.

    Yang, Xuan / Smith, Jeffery L / Beck, Michael T / Wilkinson, Jennifer M / Michaud, Ani / Vasta, James D / Robers, Matthew B / Willson, Timothy M

    Molecules (Basel, Switzerland)

    2023  Volume 28, Issue 7

    Abstract: PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential antitarget of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target ... ...

    Abstract PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential antitarget of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1, we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe
    MeSH term(s) Protein Serine-Threonine Kinases ; Cell Cycle Proteins/metabolism ; Protein Kinases ; Cell Proliferation ; Mitosis ; Protein Kinase Inhibitors/pharmacology
    Chemical Substances Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Cell Cycle Proteins ; Protein Kinases (EC 2.7.-) ; Protein Kinase Inhibitors
    Language English
    Publishing date 2023-03-25
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules28072950
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells.

    Yang, Xuan / Smith, Jeffery L / Beck, Michael T / Wilkinson, Jennifer M / Michaud, Ani / Vasta, James D / Robers, Matthew B / Willson, Timothy M

    bioRxiv : the preprint server for biology

    2023  

    Abstract: PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential anti target of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target ... ...

    Abstract PLK1 is a protein kinase that regulates mitosis and is both an important oncology drug target and a potential anti target of drugs for the DNA damage response pathway or anti-infective host kinases. To expand the range of live cell NanoBRET target engagement assays to include PLK1 we developed an energy transfer probe based on the anilino-tetrahydropteridine chemotype found in several selective PLK inhibitors. Probe 11 was used to configure NanoBRET target engagement assays for PLK1, PLK2, and PLK3 and measure the potency of several known PLK inhibitors. In cell target engagement for PLK1 was in good agreement with the reported cellular potency for inhibition of cell proliferation. Probe 11 enabled investigation of the promiscuity of adavosertib, which had been described as a dual PLK1/WEE1 inhibitor in biochemical assays. Live cell target engagement analysis of adavosertib by NanoBRET demonstrated PLK activity at micromolar concentrations but only selective engagement of WEE1 at clinically relevant doses.
    Language English
    Publishing date 2023-03-07
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.02.25.529946
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3.

    Galal, Kareem A / Krämer, Andreas / Strickland, Benjamin G / Smith, Jeffery L / Dickmander, Rebekah J / Moorman, Nathaniel J / Willson, Timothy M

    bioRxiv : the preprint server for biology

    2023  

    Abstract: We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4'-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, ...

    Abstract We report the synthesis of 2,6-disubstituted pyrazines as potent cell active CSNK2A inhibitors. 4'-Carboxyphenyl was found to be the optimal 2-pyrazine substituent for CSNK2A activity, with little tolerance for additional modification. At the 6-position, modifications of the 6-isopropylaminoindazole substituent were explored to improve selectivity over PIM3 while maintaining potent CSNK2A inhibition. The 6-isopropoxyindole analogue
    Language English
    Publishing date 2023-12-05
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.12.04.569845
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships.

    Asquith, Christopher R M / East, Michael P / Laitinen, Tuomo / Alamillo-Ferrer, Carla / Hartikainen, Erkka / Wells, Carrow I / Axtman, Alison D / Drewry, David H / Tizzard, Graham J / Poso, Antti / Willson, Timothy M / Johnson, Gary L

    European journal of medicinal chemistry

    2024  Volume 271, Page(s) 116357

    Abstract: The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off- ... ...

    Abstract The oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off-target kinase. The oxindole has long been considered a promiscuous kinase inhibitor template, but across these four specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different ranging from narrow to broad spectrum kinome coverage. We synthesized a large series of analogues, utilizing quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, kinome profiling, and small-molecule x-ray structural analysis to optimize TLK2 inhibition and kinome selectivity. This resulted in the identification of several narrow spectrum, sub-family selective, chemical tool compounds including 128 (UNC-CA2-103) that could enable elucidation of TLK2 biology.
    Language English
    Publishing date 2024-04-02
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2024.116357
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 784: Show issues Location:
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  8. Article ; Online: Gram-scale synthesis of FICZ, a photoreactive endogenous ligand of the aryl hydrocarbon receptor.

    Zhang, Cunyu / Creech, Katrina L / Zuercher, William J / Willson, Timothy M

    Scientific reports

    2019  Volume 9, Issue 1, Page(s) 9982

    Abstract: Development of an efficient and scalable synthesis of 6-formylindolo[3,2-b]carbazole (FICZ), a naturally-occurring aryl hydrocarbon receptor (AhR) ligand, allowed its biological and physical properties to be studied. FICZ was shown to be the most potent ... ...

    Abstract Development of an efficient and scalable synthesis of 6-formylindolo[3,2-b]carbazole (FICZ), a naturally-occurring aryl hydrocarbon receptor (AhR) ligand, allowed its biological and physical properties to be studied. FICZ was shown to be the most potent among a series of 6-substituted indolo[3,2-b]carbazoles for activation of AhR in cells. Photostability studies of FICZ revealed a non-enzymatic mechanism for its conversion to a biologically active quinone. These results further support the hypothesis that FICZ is a light-dependent hormone that links sun exposure to regulation of biological pathways in peripheral tissues.
    MeSH term(s) Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carbazoles/chemical synthesis ; Carbazoles/chemistry ; Carbazoles/pharmacology ; Cell Line ; Drug Stability ; Humans ; Ligands ; Molecular Structure ; Photochemical Processes ; Receptors, Aryl Hydrocarbon/metabolism
    Chemical Substances 6-formylindolo(3,2-b)carbazole ; AHR protein, human ; Basic Helix-Loop-Helix Transcription Factors ; Carbazoles ; Ligands ; Receptors, Aryl Hydrocarbon
    Language English
    Publishing date 2019-07-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-019-46374-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: A Perspective on Extreme Open Science: Companies Sharing Compounds without Restriction.

    Drewry, David H / Wells, Carrow I / Zuercher, William J / Willson, Timothy M

    SLAS discovery : advancing life sciences R & D

    2019  Volume 24, Issue 5, Page(s) 505–514

    Abstract: Although the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. This perspective describes how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted ... ...

    Abstract Although the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. This perspective describes how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. The integration of open science and kinase chemogenomics has supported the study of many new potential drug targets by the scientific community.
    MeSH term(s) Chemistry, Pharmaceutical/trends ; Drug Discovery ; Genome, Human/genetics ; Humans ; Molecular Targeted Therapy/trends ; Phosphotransferases/genetics ; Phosphotransferases/therapeutic use ; Proteins/genetics ; Proteins/therapeutic use
    Chemical Substances Proteins ; Phosphotransferases (EC 2.7.-)
    Language English
    Publishing date 2019-04-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2885123-7
    ISSN 2472-5560 ; 2472-5552
    ISSN (online) 2472-5560
    ISSN 2472-5552
    DOI 10.1177/2472555219838210
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4911: Show issues Location:
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  10. Article: Concise, gram-scale synthesis of furo[2,3-b]pyridines with functional handles for chemoselective cross-coupling

    O'Byrne, Sean N / Eduful, Benjamin J / Willson, Timothy M / Drewry, David H

    Tetrahedron letters. 2020 Sept. 17, v. 61, no. 38

    2020  

    Abstract: A concise 4-step synthesis of furo[2,3-b]pyridines, with handles in the 3- and 5-positions for palladium mediated cross-coupling reactions, is described. The synthetic route has been optimized, with only one step requiring purification by column ... ...

    Abstract A concise 4-step synthesis of furo[2,3-b]pyridines, with handles in the 3- and 5-positions for palladium mediated cross-coupling reactions, is described. The synthetic route has been optimized, with only one step requiring purification by column chromatography. The route is amenable to scale-up, and was successfully executed on a multi-gram scale. Furopyridines are of growing interest in medicinal chemistry, and this route should enable easy access to the core for structure-activity relationship (SAR) studies.
    Keywords chemoselectivity ; chromatography ; cross-coupling reactions ; palladium ; pyridines ; structure-activity relationships
    Language English
    Dates of publication 2020-0917
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 204287-3
    ISSN 1873-3581 ; 0040-4039
    ISSN (online) 1873-3581
    ISSN 0040-4039
    DOI 10.1016/j.tetlet.2020.152353
    Database NAL-Catalogue (AGRICOLA)

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    Zs.A 2837: Show issues Location:
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