A Versatile DNA‐Encoded Library Platform for the Discovery of Highly Cooperative Chemical Inducers of Proximity
Bingqi Tong, Sunny A. Tang, Yifan Deng, Zhihan Nan, Alison X. Gao, Gregory A. Michaud, Simone Bonazzi, Frédéric Berst, Frédéric J. Zécri, Shuang Liu, William J. Gibson, Stuart L. SchreiberABSTRACT
Chemical‐induced proximity, particularly via molecular glues, represents a rapidly advancing therapeutic paradigm. Expanding the scope of proximity‐based therapeutics requires generalizable discovery platforms that can be easily tailored to diverse presenter proteins. Here, we report a versatile DNA‐encoded library (DEL) strategy designed to identify highly cooperative chemical inducers of proximity (CIPs) for multiple presenter proteins. By leveraging a novel precursor library constructed via on‐DNA strained allene cycloadditions, we generated three distinct CIP‐DELs biased toward Cereblon (CRBN), VHL, and FKBP12. Screening the CRBN‐focused library with BRD9 identified B67b , a novel compound that mediates ternary complex formation between CRBN and BRD9 with nanomolar potency and strong molecular glue‐like cooperativity (α >300). B67b engages BRD9 in a CRBN‐dependent manner, a characteristic of classical molecular glues, and its high cooperativity is driven by the synergistic contribution of all its structural and stereochemical components. This work establishes a scalable, generalizable framework for repurposing generic DELs into presenter‐specific screening tools, offering a powerful approach to accelerate the discovery of CIP therapeutics for a broad range of targets.