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Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug Conjugates

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2024, 146, 34, 23717-23728
    Article

    Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug Conjugates
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    • Juliana T. W. Tong
      Juliana T. W. Tong
      School of Chemical Sciences, The University of Auckland, Auckland 1010, New Zealand
      Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
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    • Makhdoom Sarwar
      Makhdoom Sarwar
      Department of Obstetrics and Gynaecology, University of Otago, Christchurch, Christchurch 8011, New Zealand
      Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
      More by Makhdoom Sarwar
    • Marzieh Ahangarpour
      Marzieh Ahangarpour
      School of Chemical Sciences, The University of Auckland, Auckland 1010, New Zealand
      Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
      More by Marzieh Ahangarpour
      Orcidhttps://orcid.org/0000-0001-5534-7106
    • Paul A. Hume
      Paul A. Hume
      Department of Obstetrics and Gynaecology, University of Otago, Christchurch, Christchurch 8011, New Zealand
      School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington 6012, New Zealand
      MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington 6012, New Zealand
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    • Geoffrey M. Williams
      Geoffrey M. Williams
      School of Chemical Sciences, The University of Auckland, Auckland 1010, New Zealand
      More by Geoffrey M. Williams
    • Margaret A. Brimble*
      Margaret A. Brimble
      School of Chemical Sciences, The University of Auckland, Auckland 1010, New Zealand
      Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
      *Email: [email protected]
      More by Margaret A. Brimble
      Orcidhttps://orcid.org/0000-0002-7086-4096
    • Iman Kavianinia*
      Iman Kavianinia
      School of Biological Sciences, The University of Auckland, Auckland 1010, New Zealand
      Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New Zealand
      *Email: [email protected]
      More by Iman Kavianinia
      Orcidhttps://orcid.org/0000-0002-2446-1376
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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2024, 146, 34, 23717–23728
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.4c04567
    Published August 15, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    In the fast-evolving landscape of targeted cancer therapies, the revolutionary class of biotherapeutics known as antibody-drug conjugates (ADCs) are taking center stage. Most clinically approved ADCs utilize cleavable linkers to temporarily attach potent cytotoxic payloads to antibodies, allowing selective payload release under tumor-specific conditions. In this study, we explored the utilization of 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), a cyclic β-diketone featuring an active alkylidene group, to develop a novel chemically labile linker. This linker was designed to exploit the difference in reduction potential between the intracellular compartment and plasma. Upon reduction of an azido trigger strategically installed neighboring the cyclic β-diketone, the resulting nucleophilic primary amine reacts with the alkylidene group facilitated by a favorable ring closure reaction in accordance with Baldwin’s rules. Consequently, this reaction enables the simultaneous release of the attached cytotoxic payload. The therapeutic utility of this novel linker strategy was demonstrated by separate conjugation of the linker to two epidermal growth factor receptor (EGFR)-targeting ligands to afford a peptide-drug conjugate and an ADC. This work comprises a significant contribution to the bioconjugation field by introducing the alkylidene cyclic β-diketone as a tunable scaffold used for the temporary conjugation of therapeutic agents to peptides and proteins.

    Copyright © 2024 American Chemical Society

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2024, 146, 34, 23717–23728
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.4c04567
    Published August 15, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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