Targeted Transcriptional Repression by Induced Proximity

Abstract Most cancer-driving proteins remain “undruggable” due to the absence of ligandable pockets and their reliance on intrinsically disordered or protein–DNA/protein–protein interactions. Transcription factors, which orchestrate oncogenic gene expression programs, are particularly challenging: they turn over rapidly, evade durable pharmacological inhibition, and resist even emerging targeted protein degradation strategies. Here, we describe a new induced-proximity therapeutic modality, Transcriptional Regulation via Active Control of 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) and the Nucleosome Remodeling and Deacetylase (NuRD) complex to transcription factor–directed ligands. An estrogen receptor (ER) TRACER potently suppressed ER transcriptional activity in breast cancer cells, downregulated canonical 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, achieving >90% inhibition of AR transcriptional activity in androgen-independent prostate cancer cells with locus-specific gene repression. We further show that TRACERs can be modularly reprogrammed to recruit alternative repressors, including PRC2. Collectively, these findings establish TRACERs as a generalizable modality to pharmacologically silence undruggable transcription factors through targeted epigenetic reprogramming, offering a powerful new strategy for treating cancers refractory to existing therapies. Competing Interest Statement DD, JM, MS, CJ, BF, FW, NP are Novartis Biomedical Research employees. DKN is a co-founder, shareholder, and scientific advisory board member for Frontier Medicines and Zenith. DKN is also on the scientific advisory board of The Mark Foundation for Cancer Research, Photys Therapeutics, Axiom Therapeutics, Oerth Bio, Apertor Pharmaceuticals, Ten30 Biosciences, and Deciphera. DKN is also an Investment Advisory Partner for a16z Bio, an Advisory Board member for Droia Ventures, and an iPartner for The Column Group.