AbstractProteolysis‐targeting chimeras (PROTACs) provide a powerful technique to degrade targeted proteins utilizing the cellular ubiquitin‐proteasome system. The major concern is the host toxicity resulting from their poor selectivity. Inducible PROTACs responding to exogenous stimulus, such as light, improve their specificity, but it is difficult for photo‐activation in deep tissues. Herein, we develop H2O2‐inducible PROTAC precursors 2/5, which can be activated by endogenous H2O2 in cancer cells to release the active PROTACs 1/4 to effectively degrade targeted proteins. This results in the intended cytotoxicity towards cancer cells while targeted protein in normal cells remains almost unaffected. The higher Bromodomain‐containing protein 4 (BRD4) degradation activity and cytotoxicity of 2 towards cancer cells is mainly due to the higher endogenous concentration of H2O2 in cancer cells (A549 and H1299), characterized by H2O2‐responsive fluorescence probe 3. Western blot assays and cytotoxicity experiments demonstrate that 2 degrades BRD4 more effectively and is more cytotoxic in H2O2‐rich cancer cells than in H2O2‐deficient normal cells. This method is also extended to estrogen receptor (ER)‐PROTAC precursor 5, showing H2O2‐dependent ER degradation ability. Thus, we establish a novel strategy to induce targeted protein degradation in a H2O2‐dependent way, which has the potential to improve the selectivity of PROTACs.

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