A Versatile DNA‐Encoded Library Platform for the Discovery of Highly Cooperative Chemical Inducers of Proximity

Abstract

ABSTRACT 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.