Discovery of BRD9 Molecular Glue Degraders That Spare Cardiomyocytes

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.