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

  • 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
  • Donald C. Porter
    Donald C. Porter
    Senex Biotechnology, Inc., Columbia, South Carolina 29208, United States
  • Aleksei Mindich
    Aleksei Mindich
    CSC BIOCAD, Strelna, Saint-Petersburg 198515, Russia
    Biotechnology Department, Sirius University of Science and Technology, Sochi 354340, Russia
  • Svetlana Gorbunova
    Svetlana Gorbunova
    CSC BIOCAD, Strelna, Saint-Petersburg 198515, Russia
  • 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
  • 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]
  • , and 
  • 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]
Cite this: J. Med. Chem. 2022, 65, 4, 3420–3433
Publication Date (Web):February 3, 2022
https://doi.org/10.1021/acs.jmedchem.1c01951
Copyright © 2022 American Chemical Society

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    Supporting Info (6)»

    Abstract

    Abstract Image

    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.

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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.

    Cited By

    This article is cited by 5 publications.

    1. Kai-Hong Lv, Li Chen, Ke-hua Zhao, Jia-Ming Yang, Sheng-Jiao Yan. Cu-Catalyzed Decarboxylative Annulation of N-Phenylglycines with Maleimides: Synthesis of 1H-Pyrrolo[3,4-c]quinoline-1,3(2H)-diones. The Journal of Organic Chemistry 2023, 88 (4) , 2358-2366. https://doi.org/10.1021/acs.joc.2c02757
    2. Xing Chen, Yaoyao Yan, Xiu Cheng, Zhaoyan Zhang, Chuanbiao He, Dan Wu, Dahai Zhao, Xinhua Liu. A novel CDK8 inhibitor with poly-substituted pyridine core: Discovery and anti-inflammatory activity evaluation in vivo. Bioorganic Chemistry 2023, 133 , 106402. https://doi.org/10.1016/j.bioorg.2023.106402
    3. Jui-Yi Hsu, Kai-Cheng Hsu, Ching Sun, Ching-Hsuan Chou, Tony Eight Lin, Tzu-Ying Sung, Hui-Ju Tseng, Shih-Chung Yen, Chia-Ron Yang, Wei-Jan Huang. Design, synthesis, and biological evaluation of indolin-2-one derivatives as novel cyclin-dependent protein kinase 8 (CDK8) inhibitors. Biomedicine & Pharmacotherapy 2023, 159 , 114258. https://doi.org/10.1016/j.biopha.2023.114258
    4. Dinesh Parshuram Satpute, Urjita Shirwadkar, Anil Kumar Tharalla, Sangita Dattatray Shinde, Gargi Nikhil Vaidya, Swarali Joshi, Priyanka Patel Vatsa, Alok Jain, Abhishek A Singh, Rachana Garg, Amit Mandoli, Dinesh Kumar. Discovery of fluorinated 2‑Styryl 4(3H)-quinazolinone as potential therapeutic hit for oral cancer. Bioorganic & Medicinal Chemistry 2023, 81 , 117193. https://doi.org/10.1016/j.bmc.2023.117193
    5. Xiaokai Ding, Amanda C. Sharko, Martina S. J. McDermott, Gary P. Schools, Alexander Chumanevich, Hao Ji, Jing Li, Li Zhang, Zachary T. Mack, Vitali Sikirzhytski, Michael Shtutman, Laura Ivers, Norma O’Donovan, John Crown, Balázs Győrffy, Mengqian Chen, Igor B. Roninson, Eugenia V. Broude. Inhibition of CDK8/19 Mediator kinase potentiates HER2-targeting drugs and bypasses resistance to these agents in vitro and in vivo. Proceedings of the National Academy of Sciences 2022, 119 (32) https://doi.org/10.1073/pnas.2201073119