Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders

Abstract Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease‐related proteins. While molecular glue degraders exhibit drug‐like properties, their discovery has traditionally been serendipitous and often requires post hoc rationalization. In this study, we demonstrate the rational, mechanism‐guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin‐dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage‐binding protein 1 (DDB1), thereby transforming a high‐molecular‐weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine‐reactive warhead to a bromodomain‐containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4‐associated factor 16 (DCAF16) E3 ligase.