# Small Molecule ERG Inhibitors for Prostate Cancer

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $653,897

## Abstract

Project Summary/Abstract
There is a critical need for more effective and durable prostate cancer treatments. Prostate cancer (PCa) is the
most frequently diagnosed cancer among men and the second leading cause of male cancer deaths in the US.
The development, progression, and recurrence of PCa is dependent on the Androgen Receptor (AR). This has
led to the use of anti-androgen therapies that reduce endogenous steroid hormone production as well as the use
of AR antagonists. Unfortunately, nearly all patients receiving this androgen deprivation therapy (ADT) develop
resistance and progress to castration resistant PCa (CRPC). The prognosis for CRPC is poor, with median
survival of ~3 years with the best medical therapy. In short, CRPC has poor treatment options and prognosis
thereafter, presenting a clear and significant need for new treatments. Ligand activated transcription factors
(TFs) aside, TFs have traditionally been viewed as “undruggable”, although this paradigm is rapidly shifting. The
targeting of TFs for drug development has tremendous potential based on their well-documented roles in cancer
stemness, immune evasion, autoregulatory driver circuits, and drug resistance. The transcription factor ERG is
the predominant target of chromosomal translocations with TMPRSS2; these gene fusions are observed in ~50%
of prostate cancer patients. As the expression of TMPRSS2 is AR regulated this gene fusion results in AR driven
over-expression of ERG in these prostate cancers. Multiple model systems have confirmed the driver nature of
ERG in prostate cancer, firmly establishing ERG as a validated therapeutic target for PCa. To that end, we are
proposing to further develop along the translational pipeline novel small molecule inhibitors of the transcription
factor ERG as a new approach for the treatment of PCa. We are proposing two Aims for this grant. Aim 1.
Optimization of small molecule inhibitors of ERG. We developed inhibitors of ERG-DNA binding with high
nanomolar to µM cellular efficacy and specificity via hetero-bivalent inhibitors that combine a fragment that
stabilizes autoinhibition of ERG with a fragment that covalently reacts with ERG. In Aim 1, we will further optimize
these inhibitors for potency and specificity. They will be evaluated for potency and selectivity within the Ets family
using biochemical assays and for cellular specificity using mass spec based chemoproteomics approaches. Aim
2. Preclinical evaluation of ERG inhibitors. We will profile effects of the inhibitors on prostate cancer cell lines
(proliferation, apoptosis, cell cycle, migration). Effects on gene expression and ERG occupancy of well-validated
target genes will be evaluated in addition to genome wide profiling of gene expression and ERG occupancy in
the genome in response to ERG inhibition. Inhibitors will be tested using an ex vivo prostate cancer patient tissue
model and patient derived xenografts.

## Key facts

- **NIH application ID:** 10999567
- **Project number:** 1R01CA282472-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** JOHN Hackett BUSHWELLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $653,897
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999567

## Citation

> US National Institutes of Health, RePORTER application 10999567, Small Molecule ERG Inhibitors for Prostate Cancer (1R01CA282472-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10999567. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*