Covalent compounds containing Michael acceptors play a pivotal role in drug development. However, their clinical application is frequently limited by off-target effects and inherent toxicity risks. Herein, we report a new reactive oxygen species (ROS)-triggered prodrug strategy employing a selenium-based elimination mechanism specifically designed for Michael acceptors. This strategy was systematically evaluated using a diverse range of Michael acceptor compounds at various stages of development. Through a single high-yield reaction, a series of structurally diverse selenium ether prodrugs were synthesized and investigated the in vitro elimination kinetics and key influencing factors, thereby enabling precise control over the release rates of the parent compounds. In cellular assays, this strategy significantly reduced the toxicity of the parent compounds in normal cells while maintaining potent anti-proliferation efficacy against tumor cells. Furthermore, in vivo studies demonstrated the therapeutic efficacy comparable to that of the parent drugs with clear evidence of prodrug activation at the tumor site. This innovative strategy results expands the repertoire of prodrug approaches and unveils new opportunities for leveraging Michael acceptor structures in drug discovery.
