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Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B
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    Discovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B
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    • Gerrit Wilms
      Gerrit Wilms
      Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany
      More by Gerrit Wilms
    • Kevin Schofield
      Kevin Schofield
      Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United States
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Shayna Maddern
      Shayna Maddern
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Christopher Foley
      Christopher Foley
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Yeng Shaw
      Yeng Shaw
      Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United States
      More by Yeng Shaw
    • Breland Smith
      Breland Smith
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • L. Emilia Basantes
      L. Emilia Basantes
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Katharina Schwandt
      Katharina Schwandt
      Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany
    • Aaron Babendreyer
      Aaron Babendreyer
      Institute of Molecular Pharmacology, RWTH Aachen University, Aachen 52074, Germany
    • Timothy Chavez
      Timothy Chavez
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Nicholas McKee
      Nicholas McKee
      Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United States
    • Vijay Gokhale
      Vijay Gokhale
      BIO5 Institute, The University of Arizona, Tucson, Arizona 85721, United States
    • Sebastian Kallabis
      Sebastian Kallabis
      Core Facility Translational Proteomics, Institute of Innate Immunity, University Hospital Bonn, Bonn 53127, Germany
    • Felix Meissner
      Felix Meissner
      Department of Systems Immunology and Proteomics, Institute of Innate Immunity, University Hospital Bonn, Bonn 53127, Germany
    • Samantha N. Rokey
      Samantha N. Rokey
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Travis Dunckley
      Travis Dunckley
      ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, Arizona 85281, United States
    • William R. Montfort
      William R. Montfort
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
    • Walter Becker*
      Walter Becker
      Institute of Pharmacology and Toxicology, RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany
      *Email: [email protected]
    • Christopher Hulme*
      Christopher Hulme
      Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United States
      Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
      *Email: [email protected]
    Other Access OptionsSupporting Information (3)

    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 19, 17259–17289
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c01130
    Published September 30, 2024
    Copyright © 2024 American Chemical Society

    Abstract

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    Small-molecule-induced protein degradation has emerged as a promising pharmacological modality for inactivating disease-relevant protein kinases. DYRK1A and DYRK1B are closely related protein kinases that are involved in pathological processes such as neurodegeneration, cancer development, and adaptive immune homeostasis. Herein, we report the development of the first DYRK1 proteolysis targeting chimeras (PROTACs) that combine a new ATP-competitive DYRK1 inhibitor with ligands for the E3 ubiquitin ligase component cereblon (CRBN) to induce ubiquitination and subsequent proteasomal degradation of DYRK1A and DYRK1B. The lead compound (DYR684) promoted fast, efficient, potent, and selective degradation of DYRK1A in cell-based assays. Interestingly, an enzymatically inactive splicing variant of DYRK1B (p65) resisted degradation. Compared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of downstream signaling. Collectively, our results identify DYRKs as viable targets for PROTAC-mediated degradation and qualify DYR684 as a useful chemical probe for DYRK1A and DYRK1B.

    Copyright © 2024 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.4c01130.

    • SMILES codes (PDB ID Code for the DYRK1A–DYR530 complex: 8T2H) (CSV)

    • Kinomescan profiling XLSX)

    • CRBN binding data, DCAF7 quantitation studies, GFP-DYRK1 degradation, DYRK1B-p69 and p65 structural models, proteomics studies, NMR and HPLC spectra of ligands/intermediates, and the homology model of the ternary complex (PDF)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 19, 17259–17289
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c01130
    Published September 30, 2024
    Copyright © 2024 American Chemical Society

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