Targeted Transcriptional Repression by Induced Proximity.

Many transcription factors are considered "undruggable" and challenging targets due to the absence of ligandable pockets, large swaths of intrinsically disordered regions, and rapid turnover. Here, we describe a new induced-proximity therapeutic modality, Transcriptional Repression via Active Chemical Epigenetic Reprogramming (TRACER), that enforces locus-specific transcriptional silencing by recruiting endogenous corepressor complexes to transcription factor binding sites. We developed small-molecule TRACERs that tether methyl-CpG binding domain protein 2 (MBD2), a component of the Nucleosome Remodeling and Deacetylase (NuRD) complex, to transcription factor-directed ligands. Recruitment of the NuRD complex by an estrogen receptor (ER) TRACER potently suppressed ER transcriptional activity in breast cancer cells, downregulated ER target genes, and required MBD2 and histone deacetylase (HDAC1/2) for activity, confirming on-target epigenetic repression. Extending this approach to prostate cancer, an androgen receptor (AR) TRACER transcriptionally repressed both full-length AR and the drug-resistant truncation variant, AR-V7, thereby achieving >90% inhibition of AR-dependent transcription in androgen-independent prostate cancer cells with locus-specific gene repression. Collectively, these findings establish TRACERs as a generalizable modality to pharmacologically silence transcription factors through targeted epigenetic reprogramming, offering a powerful strategy for treating cancers refractory to existing therapies.