Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug ConjugatesClick to copy article linkArticle link copied!
- Juliana T. W. TongJuliana T. W. TongSchool of Chemical Sciences, The University of Auckland, Auckland 1010, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New ZealandMore by Juliana T. W. Tong
- Makhdoom SarwarMakhdoom SarwarDepartment of Obstetrics and Gynaecology, University of Otago, Christchurch, Christchurch 8011, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New ZealandMore by Makhdoom Sarwar
- Marzieh AhangarpourMarzieh AhangarpourSchool of Chemical Sciences, The University of Auckland, Auckland 1010, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New ZealandMore by Marzieh Ahangarpour
- Paul A. HumePaul A. HumeDepartment of Obstetrics and Gynaecology, University of Otago, Christchurch, Christchurch 8011, New ZealandSchool of Chemical and Physical Sciences, Victoria University of Wellington, Wellington 6012, New ZealandMacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington 6012, New ZealandMore by Paul A. Hume
- Geoffrey M. WilliamsGeoffrey M. WilliamsSchool of Chemical Sciences, The University of Auckland, Auckland 1010, New ZealandMore by Geoffrey M. Williams
- Margaret A. Brimble*Margaret A. Brimble*Email: [email protected]School of Chemical Sciences, The University of Auckland, Auckland 1010, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New ZealandMore by Margaret A. Brimble
- Iman Kavianinia*Iman Kavianinia*Email: [email protected]School of Biological Sciences, The University of Auckland, Auckland 1010, New ZealandMaurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1010, New ZealandMore by Iman Kavianinia
Abstract
![Abstract Image](/cms/10.1021/jacs.4c04567/asset/images/medium/ja4c04567_0012.gif)
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.
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