Pan-GATA molecular glues as novel tools for targeted degradation of GATA3in ER+breast cancers

GATA3, in conjunction with ESR1, is a functional dependency in ER positive luminal breast cancers. Pooled shRNA and CRISPR screens across a large panel of cancer cell lines reveal GATA3 dependency in the ER positive breast cancer context. Here we demonstrate that inducible knockdown of GATA3 leads to pronounced growth inhibition in vitro and in vivo in ER-positive breast cancer models. RNA-seq and CHIP-seq analysis show considerable overlap in differentially expressed genes upon knockdown of either transcription factors and co-occupancy of GATA3 and ER on chromatin. In addition, GATA3 knockdown led to depletion of ER binding to chromatin suggesting a concerted mechanism by which both transcription factors work together to regulate gene expression and promote tumor growth. Direct targeting of GATA3 with small molecules has posed significant challenges due to absence of suitable binding sites and lack of secondary structure beyond its DNA binding domain (DBD). GATA3 contains three CxxCG motifs within its DBD which we hypothesized to be recognized by CRBN E3 ligase for inducing targeted cellular degradation of GATA3. We report on the discovery of a primary glue hit able to form a ternary complex with CRBN and GATA3 and subsequently the progression to glue degraders via biophysical, cellular profiling, and structure-based optimization. GATA3 molecular glue degraders show significant efficacy in ER-positive breast cancer models, both in vitro and in vivo. Our study revealed a conserved recruitment and degradation mechanism across GATA family members, opening new avenues for targeting transcriptional dependencies beyond GATA3. These findings introduce a powerful chemical toolbox to further probe GATA biology and establish GATA3 as a tractable and therapeutically relevant target for future drug development efforts.