DNA‐Damage‐Response‐Targeting Mitochondria‐Activated Multifunctional Prodrug Strategy for Self‐Defensive Tumor Therapy.

We report a novel multifunctional construct, <bold>M1</bold>, designed explicitly to target the DNA damage response in cancer cells. <bold>M1</bold> contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH‐sensitive linker. Further conjugation of the triphenylphosphonium moiety allows <bold>M1</bold> to undergo specific activation in the mitochondria, where mitochondria‐mediated apoptosis is observed. Moreover, <bold>M1</bold> has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A‐activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5‐fluorouracil (5‐FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft‐bearing mice that have a low response rate to 5‐FU show a prominent effect with <bold>M1</bold>, emphasizing the importance of DNA damage response targeting strategies using tumor‐specific microenvironment‐activatable systems. [ABSTRACT FROM AUTHOR]