Disease-causing mutations frequently disrupt regulatory protein–protein interactions. In the Research Article (e12791), Xiulei Mo and co-workers exploit a mutation-generated neo-cysteine as a covalent handle to repair such defects. In this case study, a neo-cysteine targeted molecular glue (neoCMG) restores the mutant SMAD4–SMAD3 interface and reactivates tumor-suppressive signaling. This proof-of-concept establishes a generalizable strategy for targeted protein restoration in cancer and other diseases.
Kumari et al. (Thu,) studied this question.