# Defining the Role of BPTF Epigenetic Reader Domains in Cancer

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $294,385

## Abstract

The long term goal in this research is to inhibit the function of epigenetic effector or “reader” domains within
a bromodomain and-PHD-finger-containing transcription factor, BPTF. We hypothesize BPTF, via its chromatin
binding and remodeling function, controls an essential regulatory network that supports cell proliferation and
cell cycle progression in cancer. Our preliminary data using BPTF genetic knockdowns and small molecule
inhibitors supports a tumorigenic role of BPTF in breast cancer, consistent with findings in melanoma, bladder,
lung, and pancreatic cancer. The inhibition of the oncogenic function of BPTF is highly significant, and offers a
new molecular target for cancer therapy. The goals of this research are to determine the the role of
bromodomain function by developing small molecule inhibitors and testing their activity using biophysical,
biochemical, and cell-based models. Using shRNA and lead molecule S-AU1, we have established
transcriptional reporter, cellular proliferation, and RNAseq assays in breast cancer cell lines as new tools to
study the role of our molecules in a cellular setting. To complement traditional genetic approaches, a “chemical
knockout” tool will also be used for recruiting a ubiquitin ligase to BPTF using bifunctional molecules containing
a bromodomain-targeting group and an E3-ubiquitin ligase ligand for inducing proteosomal degradation.
 The innovation behind our approach uses a new multi-protein 19F NMR protein-based methodology for the
discovery of isoform selective bromodomain inhibitors. Due to the hyper-responsive nature of fluorine to ligand
binding, the result is a rapid 1D NMR experiment, that is well-suited for structure-based small molecule studies.
Due to the simplicity of the NMR spectrum, highly homologous BPTF and Brd4 bromodomains will be tested
together to readily assess selectivity of optimized molecules. This method has already led to the discovery of
the first small molecule for the BPTF bromodomain, AU1. This molecule will be further optimized in addition to
molecules from a parallel ligand discovery platform using small molecule microarrays in Aims 1 and 2. In aim
3, a new bifunctional molecule based on AU1 is proposed for recruiting enzymatic functionality of ubiquitin
ligases for selective proteolytic degradation of BPTF.
 This proposal has broad biomedical significance as a general method for early lead discovery and studies
of epigenetic reader domains important in human health and disease. Although the role of the BPTF protein in
cancer has been established, the first potent chemical probes for BPTF reader domains have potential for high
impact as new chemical tools for inhibiting cancer progression. To address this goal, we have established a
team of experts in their respective fields of chemical biology, cancer biology, and structural biology. Given that
transcription factors represent a major class of potential drug targets, our new 19F NMR small molecule
discovery method a...

## Key facts

- **NIH application ID:** 9840485
- **Project number:** 5R01GM121414-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** William Charles Krause Pomerantz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $294,385
- **Award type:** 5
- **Project period:** 2017-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840485

## Citation

> US National Institutes of Health, RePORTER application 9840485, Defining the Role of BPTF Epigenetic Reader Domains in Cancer (5R01GM121414-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840485. Licensed CC0.

---

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