A Bioorthogonal Prodrug–Prodrug Strategy for Dual Activation Via Retro-Cope/Cope Elimination

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.