Decoy-PROTAC for specific degradation of “Undruggable” STAT3 transcription factor

Abstract Signal transducer and activator of transcription 3 (STAT3) is widely recognized as an attractive target for cancer therapy due to its significant role in the initiation and progression of tumorigenesis. However, existing STAT3 inhibitors have suffered from drawbacks including poor efficacy, limited specificity, and undesirable off-target effects, due to the challenging nature of identifying active sites or allosteric regulatory pockets on STAT3 amenable to small-molecule inhibition. In response to these obstacles, we utilize the innovative proteolysis targeting chimera (PROTAC) technology to create a highly specific decoy-targeted protein degradation system for STAT3 protein, termed D-PROTAC. This system fuses DNA decoy that targets STAT3 with an E3 ligase ligand, utilizing a click chemistry approach. Experimental results demonstrate that D-PROTAC efficiently mediates the degradation of the STAT3 protein across various cancer cell types, leading to the downregulation of crucial downstream STAT3 targets, inhibiting tumor cell growth, triggering cell cycle arrest and apoptosis, and suppressing tumor immune evasion. Furthermore, D-PROTAC is capable of achieving significant tumor suppression in xenograft models. Overall, our research validates that D-PROTAC can successfully target and eliminate the “undruggable” STAT3, showcasing specificity and potent antitumor effects. This strategy will suggest a promising avenue for the development of targeted therapies against the critical functions of STAT3 in human cancers and potentially other diseases.