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Small molecules can mimic genetic mutational effects, creating neo\u2010surfaces and acting as molecular glues to mediate neoPPIs and reprogram biological circuitry. This convergence of genomic alterations and chemical interventions highlights a strategy for targeting disease\u2010associated mutations using neo\u2010amino acid residue\u2010directed molecular glues. Among these, neo\u2010cysteine at the protein\u2010protein interaction (PPI) interface represents unique opportunities to develop covalent molecular glues. Despite this promise, identifying neo\u2010cysteine molecular glues (neoCMGs) remains challenging. Here, we report the discovery of a neoCMG through a systematic chemical screening approach, using SMAD4, a frequently mutated tumor suppressor gene, as a model system. We established a robust PPI biosensor assay for high\u2010throughput chemical screening, leading to the identification of neoCMG101. Biophysical and biochemical characterization revealed that neoCMG101 selectively and covalently modifies the neo\u2010C361 residue on SMAD4, enhance SMAD4\u2010R361C\/SMAD3 PPI and restore SMAD\u2010dependent transcriptional activity. This work establishes the feasibility of leveraging neo\u2010cysteine\u2010directed molecular glues to restore mutant PPIs, supporting a generalizable strategy for identifying neoCMG hits through unbiased screening. Such an approach provides a framework for targeting mutation\u2010disrupted signaling networks in cancer and other diseases.<\/jats:p>","DOI":"10.1002\/anie.202512791","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T06:05:17Z","timestamp":1767333917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neo\u2010Cysteine Molecular Glues for Targeting Mutated SMAD4 Protein"],"prefix":"10.1002","volume":"65","author":[{"given":"Pooja","family":"Kumari","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia 30322 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Hyeun","family":"Oum","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology Emory University School of Medicine  Atlanta Georgia 30322 USA"},{"name":"Emory Chemical Biology 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