# Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2022 · $525,537

## Abstract

!
!
!
!
PROJECT SUMMARY
 Hormonal therapies have been revolutionary in the treatment of women with estrogen receptor positive
(ER+) breast cancers, greatly enhancing survival. ER-targeted hormonal therapies include selective
estrogen receptor modulators SERMs, such as tamoxifen, and selective estrogen receptor downregulators
(SERDs), such as fulvestrant, whereas aromatase inhibitors block the biosynthesis of estrogen. These
therapies have significant side effects, and their prolonged use can lead to chemoresistance in about one-
third of treated women, often resulting in more aggressive cancers. Furthermore, tamoxifen use is
associated with increased incidence of endometrial thickening and hyperplasia, polyps and cancer. Recent
studies have identified novel pathways involving the 7-transmembrane spanning G protein-coupled receptor
GPER in patients undergoing SERM/SERD therapies. Cross-reactive pharmacological agonism of GPER
contributes to both hormonal resistance and off-target effects in the uterus as all clinically approved anti-
estrogens act as agonists for GPER and stimulate these pathways. This critical issue of ER/GPER
selectivity has not been addressed in the development of SERM and SERD drugs. In our previous work, we
discovered and characterized novel selective ligands for GPER that do not bind ERa or ERb.Recently, we
discovered a novel small molecule that for the very first-time targets ER without interference of GPER.
 As current anti-estrogens do not discriminate between ERa/b and GPER, our newly identified small
molecule affords the opportunity to create novel ligands and therapeutic agents to selectively target ERa.
Through chemical modifications to this first-generation ERa-selective compound, we have improved the
affinity, receptor-selectivity and antagonist/agonist profile with the ultimate goal of creating truly ERa-
selective antagonists. The specific aims of this proposal are to: 1. Synthesize and resolve the bioactive
enantiomer of optimized ERa-targeted AB-SERD compounds with GPER anti-selectivity; 2. Prioritize
compounds through in vitro methods including receptor binding, cell signaling, proliferation and toxicity and
3. Determine in vivo anti-tumor and ADMET properties of lead compounds, employing ER-dependent and
anti-hormone-resistant transgenic, xenograft and PDX tumors.
 The successful completion of these studies will identify innovative enantiospecific compounds as
unique pharmacological tools for delineating the individual functions of ER and GPER, and also initiating the
development of first-in-class therapeutic agents, with the goal of reducing anti-hormone resistant recurrence
of breast cancer, enhancing survival and the quality of life for the greater than 200,000 women annually
diagnosed with ER-positive breast cancer.
!"#$%&'()*++,"-./01'",&'( !,2%(3(

## Key facts

- **NIH application ID:** 10521965
- **Project number:** 2R01CA194496-06
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** JEFFREY B ARTERBURN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $525,537
- **Award type:** 2
- **Project period:** 2016-09-07 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521965

## Citation

> US National Institutes of Health, RePORTER application 10521965, Molecular Mechanisms and Applications of Novel ER/GPER-selective Ligands (2R01CA194496-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10521965. Licensed CC0.

---

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