🚀 Thrilled to share our latest bioRxiv & medRxiv preprint from the Nomura Research Group, Molecular Therapeutics Initiative, and the Novartis-Berkeley Translational Chemical Biology Institute!

We introduce TRACERs (Transcriptional Regulation via Active Control of Epigenetic Reprogramming): a new fully small-molecule-based induced-proximity therapeutic modality that epigenetically silences transcription factors by recruiting endogenous corepressor complexes for locus-specific transcriptional repression.

Our work demonstrates that TRACERs can potently and selectively repress estrogen receptor (ER) and androgen receptor (AR/AR-V7) programs, thereby paving the way for pharmacologically silencing “undruggable” transcription factors through targeted epigenetic reprogramming.

Most strikingly, in androgen-independent prostate cancers expressing both AR and the “undruggable” truncation variant AR-V7 — where current AR antagonists and modulators (binding only to the ligand-binding domain, absent in AR-V7) inhibit AR transcriptional activity by only ~40% — our AR/AR-V7 TRACER, which links an AR SARM to an MBD2 recruiter, suppresses >90% of AR transcriptional activity!

We also demonstrate that we can recruit other corepressor complexes, such as the polycomb repressor complex with PRC2 inhibitors, for TRACER applications.

This establishes a new therapeutic modality – using small-molecule-induced proximity for targeted epigenetic reprogramming – to silence transcriptional networks long considered out of reach. A potential blueprint for pharmacologically “turning off” disease-driving transcription factors. 

🎉 Huge congratulations to first author Christian E. Stieger for leading this remarkable effort!

 🙏 Grateful to Novartis Science and The Mark Foundation for Cancer Research for their support! 

Also thanks to Molecular Therapeutics Initiative, College of Chemistry UC Berkeley, #BerkeleyMCB, and University of California, Berkeley!

🔗 https://www.biorxiv.org/content/10.1101/2025.10.22.680877v1