A Self-Assembled\nNano-Molecular Glue (Nano-mGlu) Enables\nGSH/H<sub>2</sub>O<sub>2</sub>‑Triggered Targeted Protein Degradation\nin Cancer Therapy

Molecular\nglues are promising protein-degrading agents that hold\ngreat therapeutic potential but face significant challenges in rational\ndesign, effective synthesis, and precise targeting of tumor sites.\nIn this study, we first overcame some of these limitations by introducing\na fumarate-based molecular glue handle onto specific ligands of therapeutic\nkinases (TBK1, FGFR, and Bcr-Abl), resulting in the effective degradation\nof these important cancer targets. Despite the broad applicability\nof the strategy, we unexpectedly discovered potent and widespread\ncytotoxicity across various cell lines, including noncancerous ones,\nrendering it less effective in cancer therapy. To address this critical\nissue, we next developed a self-assembled nanoparticle-based molecular\nglue (nano-mGlu) based on one of the newly discovered Bcr-Abl-degrading\nmolecular glues (<b>H1-mGlu</b>). We showed that the resulting\nnano-mGlu (named <b>Cle-NP</b>) was able to release <b>H1-mGlu</b> in vitro in the presence of a high concentration of GSH or H<sub>2</sub>O<sub>2</sub> (commonly found in the tumor microenvironment).\nSubsequent in vivo antitumor studies with a K562-xenografted mouse\nmodel indicated that <b>Cle-NP</b> was highly effective in tumor-specific\ndegradation of endogenous Bcr-Abl expressed in K562 cells, leading\nto eventual tumor regression while maintaining good biosafety profiles.\nWith key advantages of generality in molecular glue design, targeted\ndelivery (e.g., <b>H1-mGlu</b>), potent antitumor activity partially\ninduced by target-specific degradation, and minimized collateral damage\nto healthy tissues, our self-assembled nano-mGlu strategy thus provides\na novel approach that might hold a significant promise for effective\nand personalized cancer therapy.