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A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics

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    A Selective and Orally Bioavailable Quinoline-6-Carbonitrile-Based Inhibitor of CDK8/19 Mediator Kinase with Tumor-Enriched Pharmacokinetics
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    • Li Zhang
      Li Zhang
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      More by Li Zhang
    • Chen Cheng
      Chen Cheng
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      More by Chen Cheng
    • Jing Li
      Jing Li
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      More by Jing Li
    • Lili Wang
      Lili Wang
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      More by Lili Wang
    • Alexander A. Chumanevich
      Alexander A. Chumanevich
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      More by Alexander A. Chumanevich
    • Donald C. Porter
      Donald C. Porter
      Senex Biotechnology, Inc., Columbia, South Carolina 29208, United States
      More by Donald C. Porter
    • Aleksei Mindich
      Aleksei Mindich
      CSC BIOCAD, Strelna, Saint-Petersburg 198515, Russia
      Biotechnology Department, Sirius University of Science and Technology, Sochi 354340, Russia
      More by Aleksei Mindich
    • Svetlana Gorbunova
      Svetlana Gorbunova
      CSC BIOCAD, Strelna, Saint-Petersburg 198515, Russia
      More by Svetlana Gorbunova
    • Igor B. Roninson
      Igor B. Roninson
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      Senex Biotechnology, Inc., Columbia, South Carolina 29208, United States
      More by Igor B. Roninson
      Orcidhttps://orcid.org/0000-0002-9211-1327
    • Mengqian Chen*
      Mengqian Chen
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      Senex Biotechnology, Inc., Columbia, South Carolina 29208, United States
      *Email: [email protected]
      More by Mengqian Chen
      Orcidhttps://orcid.org/0000-0003-1706-9509
    • Campbell McInnes*
      Campbell McInnes
      Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States
      *Email: [email protected]
      More by Campbell McInnes
      Orcidhttps://orcid.org/0000-0002-5592-9082
    Other Access OptionsSupporting Information (6)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 4, 3420–3433
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c01951
    Published February 3, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    Senexins are potent and selective quinazoline inhibitors of CDK8/19 Mediator kinases. To improve their potency and metabolic stability, quinoline-based derivatives were designed through a structure-guided strategy based on the simulated drug–target docking model of Senexin A and Senexin B. A library of quinoline-Senexin derivatives was synthesized to explore the structure–activity relationship (SAR). An optimized compound 20a (Senexin C) exhibits potent CDK8/19 inhibitory activity with high selectivity. Senexin C is more metabolically stable and provides a more sustained inhibition of CDK8/19-dependent cellular gene expression when compared with the prototype inhibitor Senexin B. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) evaluation using a novel tumor-based PD assay showed good oral bioavailability of Senexin C with a strong tumor-enrichment PK profile and tumor-PD marker responses. Senexin C inhibits MV4-11 leukemia growth in a systemic in vivo model with good tolerability.

    Copyright © 2022 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01951.

    • Molecular modeling of compound 20b; Kd and binding kinetics of Senexin B/Senexin C for CDK8/19; PK/PD analysis of Senexin B; kinase selectivity panel data for Senexin C; qPCR primer sequences; synthetic procedures; characterization of compounds 8a–8j and 20a–20n; and LC–MS data for the determination of purity (PDF)

    • Molecular docking of 8a to CDK8 (4F7S) (PDB)

    • Molecular docking of Senexin A to CDK8 (4F7S) (PDB)

    • Molecular docking of 20a to CDK8 (4F7S) (PDB)

    • Molecular docking of Senexin B to CDK8 (4F7S) (PDB)

    • Molecular formula strings (CSV)

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 4, 3420–3433
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.1c01951
    Published February 3, 2022
    Copyright © 2022 American Chemical Society
    Request reuse permissions

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