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Here, we introduce a general framework that transforms MGD discovery from a serendipity\u2010driven endeavor into a systematic, scalable pipeline by integrating modular, in situ library assembly with direct\u2010to\u2010biology phenotypic screening. Powered by biocompatible primary amine\u2010based photoclick chemistry, this platform enables the efficient, purification\u2010free generation of over 1000 structurally diverse cereblon (CRBN)\u2010centric molecules within days directly in multi\u2010well plates, facilitating a seamless transition from chemical synthesis to biological evaluation. Applying this strategy, we rapidly identified novel CRBN\u2010based MGDs that potently and selectively degrade GSPT1 or CK1\u03b1, as well as a multi\u2010target degrader of GSPT1\/2 and stearoyl\u2010CoA desaturase (SCD). Crucially, our integrated validation highlights targeted CK1\u03b1 degradation as a promising therapeutic strategy for prostate cancer. By leveraging the abundance and structural diversity of primary amines, this scalable platform expands the accessible chemical space, circumventing the complexities of de novo rational design. Ultimately, this work provides a streamlined engine for harnessing diverse E3 ligases, accelerating the development of next\u2010generation MGDs to tackle intractable diseases.<\/jats:p>","DOI":"10.1002\/anie.3518516","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:33:49Z","timestamp":1779118429000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Scalable, Direct\u2010to\u2010Biology Platform for Accelerated Discovery of Cereblon\u2010Based Molecular Glue Degraders"],"prefix":"10.1002","volume":"65","author":[{"given":"Jia\u2010Yu","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 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