Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders

  • Angew Chem Int Ed Engl. 2025 Sep 15;64(38):e202508427. doi: 10.1002/anie.202508427.
Zhe Zhuang  #  1 ,  Woong Sub Byun  #  1 ,  Zuzanna Kozicka  2  3 ,  Katherine A Donovan  4  5 ,  Brendan G Dwyer  1 ,  Abby M Thornhill  4 ,  Hannah M Jones  1 ,  Zixuan Jiang  6 ,  Xijun Zhu  6 ,  Eric S Fischer  4  5 ,  Nicolas H Thomä  2  7 ,  Nathanael S Gray  1
Affiliations
  • 1. Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, CA, 94305, USA.
  • 2. Friedrich Miescher Institute for Biomedical Research, Basel, 4056, Switzerland.
  • 3. Department of Biology, University of Basel, Basel, 4001, Switzerland.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 6. Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
  • 7. Paternot chair in oncology, EPFL, Swiss Institute of Experimental Cancer Research (ISREC), Station 19, Lausanne, CH - 1015, Switzerland.
  • # Contributed equally.
PMID: 40626960 DOI: 10.1002/anie.202508427
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.

Keywords
Bromodomain‐containing protein 4; Cyclin‐dependent kinase 12/13; Molecular glue; Targeted protein degradation.
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