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Herein, through proteomic profiling of a CRBN\u2010binding library and rigorous structure\u2010activity relationship (SAR) refinement, we report the discovery of dWBP4\u20101: a first\u2010in\u2010class, highly selective, CRBN\u2010dependent molecular glue degrader of the spliceosome\u2010associated scaffold protein WBP4. dWBP4\u20101 induces rapid, nanomolar degradation of WBP4 via a canonical G\u2010loop\u2010mediated mechanism, exhibiting exceptional proteome\u2010wide selectivity with negligible transcriptomic or alternative splicing perturbation. Leveraging this highly specific target\u2010glue interaction, we mapped the minimal WBP4 degron to a 41\u2010amino\u2010acid sequence to establish a compact, inducible chemical\u2010genetic platform termed wTAG. When fused to diverse proteins of interest, wTAG enables robust, monotonic degradation devoid of the hook effect. While the wTAG system is highly versatile, we delineate its boundaries when applied to challenging targets like Cyclin D1, where factors such as steric hindrance, lysine availability, complex sequestration, and tag accessibility (N\u2010 vs. C\u2010terminal fusion) must be carefully interrogated. Collectively, this study highlights the discovery of a highly selective WBP4 molecular glue and translates its underlying degron into a robust tool for precise protein control.<\/jats:p>","DOI":"10.1002\/anie.1973691","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T18:42:35Z","timestamp":1785264155000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Selective and Potent First\u2010in\u2010Class CRBN\u2010Dependent Molecular Glue Degraders of WW Domain\u2010Binding Protein 4"],"prefix":"10.1002","volume":"65","author":[{"given":"Yuhang","family":"Liu","sequence":"first","affiliation":[{"name":"School of Pharmacy Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University) Ministry of Education China; Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong Yantai University  Yantai 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