Targeted Transcriptional Repression by Induced Proximity.

Area of Science:

• Oncology
• Epigenetics
• Drug Discovery

Background:

• Many cancer-driving proteins, particularly transcription factors, are undruggable due to lack of pockets and reliance on protein-DNA/protein-protein interactions.
• Transcription factors are challenging targets due to rapid turnover, resistance to inhibition, and evasion of protein degradation strategies.

Purpose of the Study:

• To introduce a novel induced-proximity therapeutic modality, TRACER, for targeted transcriptional silencing.
• To demonstrate TRACER's efficacy in silencing estrogen receptor (ER) and androgen receptor (AR) in cancer models.

Main Methods:

• Development of small-molecule TRACERs to tether MBD2 and the NuRD complex to transcription factor ligands.
• Application of ER-TRACER in breast cancer cells and AR-TRACER in prostate cancer cells.
• Modular reprogramming of TRACERs to recruit alternative repressors like PRC2.

Main Results:

• ER-TRACER potently suppressed ER transcriptional activity and downregulated target genes in breast cancer, dependent on MBD2 and HDACs.
• AR-TRACER achieved >90% inhibition of both full-length AR and AR-V7 activity in prostate cancer cells.
• TRACERs demonstrated modularity, enabling recruitment of different corepressor complexes for targeted gene repression.

Conclusions:

• TRACERs represent a generalizable modality for pharmacologically silencing undruggable transcription factors via epigenetic reprogramming.
• This approach offers a promising new strategy for treating cancers resistant to current therapies.