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However, a large fraction of proteome remains inaccessible with existing covalent probes. Herein, we incorporated various electron\u2010withdrawing groups into styrene derivatives and identified\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010nitrostyrene as a cysteine\u2010targeting reversible covalent warhead for target discovery. Through phenotypic screening and chemoproteomics platforms, we identified new ligandable sites such as C96 of SND1, C110 of PTGES2, modulating cell proliferation in an acute myeloid leukemia cell line. Moreover, incorporation of this warhead into the BRD4 inhibitor (+)\u2010JQ1 demonstrated that the covalent handle engages the novel E3 ligase tripartite motif\u2010containing 28 (TRIM28) at Cys232 residue, thereby promoting the targeted degradation. Notably, when transplanted into other protein\u2010targeting ligands, the\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010nitrostyrene warhead effectively induced protein degradation of EGFR\n                    <jats:sup>L858R\/T790M\/C797S<\/jats:sup>\n                    , PDE5, BTK, LRRK2, and BCR\u2010ABL\/c\u2010ABL without eliciting a hook effect. Importantly, the degraders demonstrate significantly enhanced antcancer effects compared to corresponding inhibitors. To our knowledge, this is the first report of small\u2010molecular degraders engaging TRIM28 to support targeted protein degradation, and provides a rational pathway for design and development of potent monovalent degraders.\n                  <\/jats:p>","DOI":"10.1002\/anie.202504813","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:55:37Z","timestamp":1749016537000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Proteome\u2010Wide Ligand and Target Discovery by Using\n                    <i>\u03b2<\/i>\n                    \u2010Nitrostyrene Electrophiles: Supporting Targeted Protein Degradation"],"prefix":"10.1002","volume":"64","author":[{"given":"Xinyao","family":"Ouyang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment International Cooperative Laboratory of Traditional Chinese Medicine Modernization 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