Discovery of BRD9 Molecular Glue Degraders That Spare Cardiomyocytes

  • J Am Chem Soc. 2025 Oct 1;147(39):35481-35492. doi: 10.1021/jacs.5c09857.
Woong Sub Byun  1 ,  Zhe Zhuang  1 ,  Anna P Hnatiuk  2 ,  Cyrus Jin  3  4 ,  Zixuan Jiang  5 ,  Kheewoong Baek  3  4 ,  Evelyn Chao  1 ,  Katherine A Donovan  3  4 ,  Eric S Fischer  3  4 ,  Mark Mercola  2 ,  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, California 94305, United States.
  • 2. Stanford Cardiovascular Institute, Department of Medicine, and Department of Chemical and Systems Biology, Stanford University, Stanford, California 94305, United States.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States.
  • 4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.
  • 5. Department of Chemistry, Stanford University, Stanford, California 94305, United States.
PMID: 40960846 DOI: 10.1021/jacs.5c09857
Abstract

Molecular glue degraders (MGDs) represent a class of drug-like small molecules that induce targeted protein degradation (TPD) by promoting selective protein-protein interactions. MGDs offer a promising therapeutic approach by selectively eliminating disease-associated proteins; however, their rational design and discovery have historically remained a significant challenge. The field remains constrained by a lack of strategies to effectively utilize ubiquitin ligases (E3s) for TPD, thus missing the therapeutic potential offered by tissue-specific E3 expression. In this study, we developed ZZ7, a molecular glue degrader that selectively degrades BRD9, a critical component of the SWI/SNF chromatin remodeling complex, specifically in synovial sarcoma cells, while sparing cardiomyocytes. The discovery of ZZ7 was driven by a "chemocentric" approach, incorporating a cysteine-reactive, reversible covalent warhead into a BRD9 Inhibitor to transform its function from inhibition to degradation. ZZ7 covalently engages DCAF16 at Cys178, an E3 Ligase that is highly expressed in synovial sarcoma cells but relatively underexpressed in human iPSC-derived cardiomyocytes, leveraging a cysteine residue that has not been previously exploited. These findings pave the way for new strategies in tissue- and disease-specific precision therapies, particularly for malignancies characterized by an elevated level of DCAF16 expression.

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