Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders

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 design of molecular glue degraders using gluing moieties. By appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviat-ing the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic gluing moiety 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 de-grader. We also showcase that attaching a cysteine-reactive warhead to a BRD4 inhibitor converts it into a degrader by recruiting the DDB1 and CUL4 associated factor 16 (DCAF16) E3 ligase.