The vast majority of cancer-driving proteins remain “undruggable” because they lack the well-defined binding pockets required for conventional small-molecule inhibitors. This challenge is particularly acute for transcription factors, which orchestrate gene expression programs that fuel cancer cell proliferation, survival, and metastasis. While recent advances in targeted protein degradation have made some progress, most transcription factors remain resistant to direct pharmacological intervention. Moreover, broader strategies that globally disrupt chromatin remodeling have also proven too toxic for clinical use. The critical question remains on how to achieve durable and selective silencing of oncogenic transcriptional programs without harming normal cells.
With support from an ASPIRE award, Dan Nomura and his team aim to develop a new therapeutic modality to meet this challenge: Targeted Transcriptional Repression by Induced Proximity, or TRACER. This platform uses heterobifunctional small molecules or molecular glues to bring transcription factors into proximity with epigenetic repressors, thereby silencing specific cancer-driving genes at their source. They will establish proof of concept for TRACER by linking transcription factor–binding ligands to co-repressor recruiters and validating their ability to repress oncogenic transcriptional loci in cancer models. They will also use covalent chemoproteomic methods to discover new combinations of transcription factor ligands and epigenetic modulators for rational TRACER design. By creating a scalable system for precise, locus-specific transcriptional repression, this project could unlock a new frontier in drug discovery, offering a way to therapeutically target previously inaccessible cancer drivers and expand the reach of precision oncology.