# Developing an Orally Bioavailable SERD for Treatment of Metastatic/Advanced Breast Cancer

> **NIH NIH U54** · XAVIER UNIVERSITY OF LOUISIANA · 2021 · $251,340

## Abstract

Project Summary
Selective estrogen receptor downregulators (SERDs) are a class of endocrine therapy agents
that act both as estrogen receptor (ER) antagonists and ER degraders effective in treating
metastatic or advanced breast cancer that disproportionately affects African American women.
Fulvestrant is the only FDA approved SERD indicated for advanced or metastatic breast cancer
both as a first line and second line endocrine agent. However, this injection only drug is poorly
bioavailable and it takes 30 days to reach its maximal steady-state plasma concentration,
limiting the clinical response rate to lower than 20% in the hormone resistant setting. An oral
SERD with greater drug exposure and faster action would bring immediate clinical benefits to
patients with advanced breast cancer. Further, in light of the recent FDA approval of fulvestrant
as a combination therapy with CDK4/6 inhibitor palbociclib for advanced breast cancer, the
clinical utility of an oral SERD in the combination treatment setting is also very significant.
Advances in oral SERDs development have been limited to nonsteroidal molecules with several
being currently evaluated in phase 1 clinical trials, yet none has advanced to phase II clinical
trials. Our lead compound, ZB716, has shown promising preclinical data in bioavailability,
efficacy, and toxicology. ZB716 binds to ER with high affinity and exerts its antiestrogenic effect
on ER-expressing breast cancer cells. In both tamoxifen naive and tamoxifen resistant breast
cancer cells, ZB716 potently inhibits cell proliferation and effectively degrades the hormone
receptor in a dose-dependent manner. In animals, we have shown that ZB716 has far superior
oral bioavailability when compared to fulvestrant. Moreover, in direct comparison to the two oral
SERDs under clinical trials, ZB716 is a stronger antiestrogen and ER-degrader. To further
advance the preclinical development of ZB716 we propose to investigate the in vivo efficacy of
ZB716 in endocrine resistant, patient derived breast tumor models that most closely resemble
clinical settings for which SERD is indicated. We will also evaluate ZB716 efficacy in
combination with a CDK4/6 inhibitor, palbociclib and investigate the mechanism of action of
ZB716 on patient-derived xenografts (PDX) expressing mutant forms of ER and determine the
binding behavior of ZB716 to mutant ERs and its modulation of ERα-coregulator interactions.
Finally, we will determine optimal reaction conditions under which ZB716 can be prepared in
larger scale, investigate its physical properties and formulation options for toxicological studies
in animals, and conduct metabolic profiling, pharmacokinetics, and bioavailability studies.
Accomplishing the proposed studies will provide key efficacy data to determine whether ZB716
is effective in treating endocrine resistant, ESR1 mutant breast cancer and whether it is a true
antiestrogen and ER degrader by acting through the ER. The studies will also demonstr...

## Key facts

- **NIH application ID:** 10078882
- **Project number:** 5U54MD007595-13
- **Recipient organization:** XAVIER UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Guangdi Wang
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,340
- **Award type:** 5
- **Project period:** 2009-09-24 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078882

## Citation

> US National Institutes of Health, RePORTER application 10078882, Developing an Orally Bioavailable SERD for Treatment of Metastatic/Advanced Breast Cancer (5U54MD007595-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078882. Licensed CC0.

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