Related Experiment Video
Updated: Nov 26, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity
Maysoun Shomali1, Jane Cheng2, Fangxian Sun2
1Sanofi, Research and Development, Cambridge, Massachusetts maysoun.shomali@sanofi.com.
Abstract:
Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.
Insights
A new oral drug, SAR439859, effectively blocks estrogen receptor (ER) signaling and degrades ER, showing promise for treating ER-positive breast cancer, including resistant forms. This novel selective estrogen receptor degrader (SERD) offers improved efficacy against both wild-type and mutant ER.
Area of Science:
- Pharmacology and Oncology
- Molecular Biology and Endocrinology
Background:
- Estrogen receptor-positive (ER+) breast cancer relies on endocrine therapy, but ER signaling persists, driving tumor progression.
- Existing selective estrogen receptor degraders (SERDs) like fulvestrant show limitations in fully blocking ER signaling, potentially due to suboptimal properties.
- Activating mutations in the estrogen receptor (ER) represent a significant mechanism of resistance to current endocrine therapies.
Purpose of the Study:
- To discover and characterize SAR439859, a novel, orally bioavailable selective estrogen receptor degrader (SERD).
- To evaluate the efficacy of SAR439859 against wild-type and mutant estrogen receptor (ER) forms, including those conferring resistance to endocrine therapy.
Main Methods:
- SAR439859 was designed with a unique fluoropropyl pyrrolidinyl side chain for enhanced ER antagonist and degrader activity.
- In vitro studies assessed SAR439859's effects on ER+ cell lines, comparing its potency to existing SERDs.
- In vivo efficacy was evaluated in mouse models of ER+ breast cancer, including those with wild-type and Y537S mutant ESR1 genes, and a patient-derived tamoxifen-resistant xenograft model.
Main Results:
- SAR439859 demonstrated potent antagonist and degradation activity against both wild-type and Y537S mutant ER.
- Compared to SERDs with cinnamic acid side chains, SAR439859 exhibited broader and superior ER inhibition and tumor cell growth suppression in vitro.
- In vivo, SAR439859 treatment led to significant tumor regression in various ER+ breast cancer models, including resistant and mutant forms.
Conclusions:
- SAR439859 is a novel oral SERD with potent anti-tumor activity against ER+ breast cancer.
- Its ability to effectively target both wild-type and mutant ER, including resistant forms, suggests significant therapeutic potential.
- SAR439859 may offer a new treatment option for patients with ER+ breast cancer, particularly those resistant to current endocrine therapies.
More Related Videos
11:13Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
08:48An In Vitro Dormancy Model of Estrogen-sensitive Breast Cancer in the Bone Marrow: A Tool for Molecular Mechanism Studies and Hypothesis Generation
Published on: June 30, 2015
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle