A Bioorthogonal Prodrug–Prodrug Strategy for Dual Activation Via Retro-Cope/Cope Elimination
Abstract
Bioorthogonal prodrug strategies with dual payload activation are pivotal for combinational therapy, yet they remain very scarce. Herein, we report a prodrug–prodrug strategy for the coactivation of a covalent inhibitor alongside a secondary chemotherapeutic agent, leveraging a tandem retro-Cope and Cope elimination. Notably, the rate constants for the initial retro-Cope elimination can be tuned to over 10 2 M –1 s –1 in certain cases. The proof of concept is firmly established for the coactivation of the EGFR covalent inhibitor osimertinib together with the chemotherapeutics doxorubicin or CA4.
Fields of Study & Subjects
Click Chemistry and Applications
Protein Degradation and Inhibitors
Nanoplatforms for cancer theranostics
Publication details
- Journal / source
- Organic Letters
- Publisher
- American Chemical Society (ACS)
- Volume
- 28
- Issue
- 21
- Pages
- 6756–6760
- Publication date
- 15 May 2026
- Language
- EN