A Scalable, Direct‐to‐Biology Platform for Accelerated Discovery of Cereblon‐Based Molecular Glue Degraders

ABSTRACT Molecular glue degraders (MGDs) offer transformative potential for expanding the druggable proteome; however, their discovery is severely impeded by mechanistic complexities that hinder rational design and synthetic bottlenecks that restrict the scale and diversity of E3 ligase‐centric compound libraries. Here, we introduce a general framework that transforms MGD discovery from a serendipity‐driven endeavor into a systematic, scalable pipeline by integrating modular, in situ library assembly with direct‐to‐biology phenotypic screening. Powered by biocompatible primary amine‐based photoclick chemistry, this platform enables the efficient, purification‐free generation of over 1000 structurally diverse cereblon (CRBN)‐centric molecules within days directly in multi‐well plates, facilitating a seamless transition from chemical synthesis to biological evaluation. Applying this strategy, we rapidly identified novel CRBN‐based MGDs that potently and selectively degrade GSPT1 or CK1α, as well as a multi‐target degrader of GSPT1/2 and stearoyl‐CoA desaturase (SCD). Crucially, our integrated validation highlights targeted CK1α 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‐generation MGDs to tackle intractable diseases.