Dysregulated transcription is a central feature of tumor biology, yet directly targeting transcription factors (TFs) with small molecules remains a major unresolved challenge. Most TFs lack druggable binding pockets, are largely intrinsically disordered, and function within dynamic, multicomponent chromatin complexes, limiting the effectiveness of conventional inhibition strategies. Nonetheless, rare clinical successes, such as therapies targeting the estrogen receptor (ER), demonstrate that transcriptional programs are high-value therapeutic targets.
The ligandability of ER has led to a diverse set of ER modulators, including what are termed selective ER degraders (SERDs), whose therapeutic activity has traditionally been attributed to induced ER protein degradation. However, this Endeavor team recently showed that these compounds work through an unexpected alternative mechanism: directly inducing SUMOylation and thereby triggering transcriptional repression through recruitment of co-repressors. Now, they will address the overarching question of whether oncogenic transcription can be broadly disrupted by exploiting a previously underappreciated mechanism: ligand-induced SUMOylation that converts active transcriptional complexes into stably repressed states.
Using an interdisciplinary approach spanning chemical biology, structural biology, biophysics, and AI-enabled molecular design, the team will dissect how small molecules induce SUMOylation of TFs such as ER, leading to chromatin immobilization and durable transcriptional silencing. These insights will guide the development of novel SUMOylation-inducing compounds and be extended to other clinically relevant TFs, including the androgen receptor in prostate cancer and additional nuclear hormone receptors.
A key objective is to generalize this strategy to currently undruggable TFs by leveraging molecular glue-like approaches that enhance interactions with the SUMOylation machinery. High-throughput chemical screening, protein engineering, and multi-omics profiling will be integrated to identify compounds that enforce TF hyper-SUMOylation and suppress oncogenic transcriptional programs.
By introducing ligand-induced SUMOylation as a new therapeutic modality, this work challenges the prevailing focus on inhibition or degradation and instead exploits a dominant-negative mechanism to achieve deeper and more durable transcriptional repression. The anticipated outcome is a broadly transferable framework for targeting transcriptional dependencies across cancers, expanding the druggable landscape and offering new treatment opportunities, particularly in therapy-resistant disease. Ultimately, this approach has the potential to deliver more effective, long-lasting therapies for cancer patients.