# Targeted disruption of estrogen receptor activation

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2021 · $80,500

## Abstract

Over 70% of breast cancers are Estrogen Receptor alpha (ERα)-positive, and current ERα-
targeted therapies singularly focus on the receptor's hormone-binding domain (HBD) to which
the drug tamoxifen binds. While initial treatments with endocrine therapies are successful for
these patients, some with advanced diseases later develop resistance, including those who
carry constitutively active ERα mutations (e.g., Y537S and D538G) in HBD. Moreover, these
drug-resistant mutations bind and respond much more less effectively than the wild-type protein
to fulvestrant, an FDA-approved first-line drug for treating ER-positive endocrine-resistant breast
cancer. As such, new drugs are needed to target ERα in locations other than the tamoxifen-
binding pocket in the HBD to overcome endocrine resistance. We recently reported the
presence of a novel functional interface that bridges the HBD and the DNA-binding domain
(DBD), two major functional units of the receptor. Disruption of the DBD-HBD bridging
interface prevents the two parts of the receptor from communicating. As such, targeting the
interface represents a “burning the bridge” strategy in the fight against ERα-positive breast
cancer.
 Drug targeting of the ERα domain-bridging interface is particularly appealing;
technologically, however, the ability to directly screen for specific ERα inhibitors requires a
way to read out structure variations at the interface. By genetically engineering fluorescent
probes to the purified receptor, we are able to determine whether or not HBD and DBD
communicate properly. This approach represents a unique assay to screen small molecule
inhibitors in vitro for their ability to disrupt the ER domain-interface, while cell-based
experiments will further provide functional characterization for selected small molecules.
Using this fluorescence assay, we will screen libraries of 2000+ FDA-approved drugs.
Because the drug development process is long and slow, this repurposing or recycling
approach is poised to jump-start the process; indeed, we have identified several molecules
that inhibit the ERα activity by targeting the DBD-HBD interface. Collectively, our proposed
“burning the bridge” strategy, armed with the ERα-specific fluorescence assay and cell-based
analyses, presents a novel approach for ERα drug targeting. In this proposal, we will conduct
in-depth functional and mechanistic studies for repurposed drugs (and their derivatives with
similar fingerprints) and further determine their impacts on constitutively active ERα mutants
found in drug-resistant ER-positive patients.

## Key facts

- **NIH application ID:** 10131781
- **Project number:** 5R03CA241977-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Sichun Yang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $80,500
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131781

## Citation

> US National Institutes of Health, RePORTER application 10131781, Targeted disruption of estrogen receptor activation (5R03CA241977-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10131781. Licensed CC0.

---

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